RBCC Red Blood Cell Collection

NF2 (SCH) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Merlin (Moesin-ezrin-radixin-like protein; Neurofibromin-2; Schwannomerlin; Schwannomin)

UniProt P35240
ID MERL_HUMAN Reviewed; 595 AA.
AC P35240; O95683; Q8WUJ2; Q969N0; Q969Q3; Q96T30; Q96T31; Q96T32;
read moreAC Q96T33; Q9BTW3; Q9UNG9; Q9UNH3; Q9UNH4;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1994, sequence version 1.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Merlin;
DE AltName: Full=Moesin-ezrin-radixin-like protein;
DE AltName: Full=Neurofibromin-2;
DE AltName: Full=Schwannomerlin;
DE AltName: Full=Schwannomin;
GN Name=NF2; Synonyms=SCH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8453669; DOI=10.1016/0092-8674(93)90406-G;
RA Trofatter J.A., Maccollin M.M., Rutter J.L., Murrell J.R., Duyao M.P.,
RA Parry D.N., Eldridge R., Kley N., Menon A.G., Pulaski K., Haase V.H.,
RA Ambrose C.M., Munroe D., Bove C., Haines J.L., Martuza R.L.,
RA Macdonald M.E., Seizinger B.R., Short M.P., Buckler A.J.,
RA Gusella J.F.;
RT "A novel moesin-, ezrin-, radixin-like gene is a candidate for the
RT neurofibromatosis 2 tumor suppressor.";
RL Cell 72:791-800(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8379998; DOI=10.1038/363515a0;
RA Rouleau G.A., Merel P., Lutchman M., Sanson M., Zucman J.,
RA Marineau C., Hoang-Xuan K., Demczuk S., Desmaze C., Plougastel B.,
RA Pulst S., Lenoir G., Bijlsma E., Fashold R., Dumanski J.P.,
RA de Jong P., Parry D., Eldrige R., Aurias A., Delattre O., Thomas G.;
RT "Alteration in a new gene encoding a putative membrane-organizing
RT protein causes neuro-fibromatosis type 2.";
RL Nature 363:515-521(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2).
RX PubMed=9817927; DOI=10.1093/hmg/7.13.2095;
RA Zucman-Rossi J., Legoix P., Der Sarjussian H., Cheret G., Sor F.,
RA Bernardi A., Cazes L., Giraud S., Lenoir G., Thomas G.;
RT "NF2 gene in neurofibromatosis type 2 patients.";
RL Hum. Mol. Genet. 7:2095-2101(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 7; 9 AND 10), AND SUBCELLULAR
RP LOCATION.
RX PubMed=10401006; DOI=10.1093/hmg/8.8.1561;
RA Schmucker B., Tang Y., Kressel M.;
RT "Novel alternatively spliced isoforms of the neurofibromatosis type 2
RT tumor suppressor are targeted to the nucleus and cytoplasmic
RT granules.";
RL Hum. Mol. Genet. 8:1561-1570(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3; 4; 5; 6 AND 8).
RX PubMed=11827459; DOI=10.1006/geno.2001.6672;
RA Chang L.-S., Akhmametyeva E.M., Wu Y., Zhu L., Welling D.B.;
RT "Multiple transcription initiation sites, alternative splicing, and
RT differential polyadenylation contribute to the complexity of human
RT neurofibromatosis 2 transcripts.";
RL Genomics 79:63-76(2002).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
RC TISSUE=Lung, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP REVIEW.
RA Marineau C., Merel P., Rouleau G.A., Thomas G.;
RT "The gene of neurofibromatosis type 2.";
RL Medecine/Sciences 11:35-42(1995).
RN [9]
RP INTERACTION WITH SLC9A3R1.
RX PubMed=9430655; DOI=10.1074/jbc.273.3.1273;
RA Murthy A., Gonzalez-Agosti C., Cordero E., Pinney D., Candia C.,
RA Solomon F., Gusella J., Ramesh V.;
RT "NHE-RF, a regulatory cofactor for Na(+)-H+ exchange, is a common
RT interactor for merlin and ERM (MERM) proteins.";
RL J. Biol. Chem. 273:1273-1276(1998).
RN [10]
RP INTERACTION WITH HGS.
RX PubMed=10861283; DOI=10.1093/hmg/9.11.1567;
RA Scoles D.R., Huynh D.P., Chen M.S., Burke S.P., Gutmann D.H.,
RA Pulst S.-M.;
RT "The neurofibromatosis 2 tumor suppressor protein interacts with
RT hepatocyte growth factor-regulated tyrosine kinase substrate.";
RL Hum. Mol. Genet. 9:1567-1574(2000).
RN [11]
RP INVOLVEMENT IN MESOM.
RX PubMed=12136076;
RA Baser M.E., De Rienzo A., Altomare D., Balsara B.R., Hedrick N.M.,
RA Gutmann D.H., Pitts L.H., Jackler R.K., Testa J.R.;
RT "Neurofibromatosis 2 and malignant mesothelioma.";
RL Neurology 59:290-291(2002).
RN [12]
RP INTERACTION WITH SGSM3.
RX PubMed=15541357; DOI=10.1016/j.bbrc.2004.10.095;
RA Lee I.K., Kim K.-S., Kim H., Lee J.Y., Ryu C.H., Chun H.J., Lee K.-U.,
RA Lim Y., Kim Y.H., Huh P.-W., Lee K.-H., Han S.-I., Jun T.-Y.,
RA Rha H.K.;
RT "MAP, a protein interacting with a tumor suppressor, merlin, through
RT the run domain.";
RL Biochem. Biophys. Res. Commun. 325:774-783(2004).
RN [13]
RP INTERACTION WITH AGAP2, AND MUTAGENESIS OF LEU-64.
RX PubMed=15598747; DOI=10.1073/pnas.0405971102;
RA Rong R., Tang X., Gutmann D.H., Ye K.;
RT "Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits
RT phosphatidylinositol 3-kinase through binding to PIKE-L.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:18200-18205(2004).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-518, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [15]
RP INTERACTION WITH DCAF1, AND UBIQUITINATION.
RX PubMed=18332868; DOI=10.1038/onc.2008.44;
RA Huang J., Chen J.;
RT "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for
RT degradation.";
RL Oncogene 27:4056-4064(2008).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [17]
RP INTERACTION WITH MPP1, AND SUBCELLULAR LOCATION.
RX PubMed=19144871; DOI=10.3181/0809-RM-275;
RA Seo P.-S., Quinn B.J., Khan A.A., Zeng L., Takoudis C.G., Hanada T.,
RA Bolis A., Bolino A., Chishti A.H.;
RT "Identification of erythrocyte p55/MPP1 as a binding partner of NF2
RT tumor suppressor protein/Merlin.";
RL Exp. Biol. Med. 234:255-262(2009).
RN [18]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH VPRBP AND THE
RP CUL4A-RBX1-DDB1-VPRBP/DCAF1 E3 UBIQUITIN-PROTEIN LIGASE COMPLEX,
RP PHOSPHORYLATION, MUTAGENESIS OF LEU-64 AND SER-518, CHARACTERIZATION
RP OF VARIANT ARG-46, AND CHARACTERIZATION OF VARIANTS NF2 SER-62 AND
RP PRO-141.
RX PubMed=20178741; DOI=10.1016/j.cell.2010.01.029;
RA Li W., You L., Cooper J., Schiavon G., Pepe-Caprio A., Zhou L.,
RA Ishii R., Giovannini M., Hanemann C.O., Long S.B.,
RA Erdjument-Bromage H., Zhou P., Tempst P., Giancotti F.G.;
RT "Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin
RT ligase CRL4(DCAF1) in the nucleus.";
RL Cell 140:477-490(2010).
RN [19]
RP FUNCTION.
RX PubMed=20159598; DOI=10.1016/j.devcel.2009.12.012;
RA Yu J., Zheng Y., Dong J., Klusza S., Deng W.-M., Pan D.;
RT "Kibra functions as a tumor suppressor protein that regulates Hippo
RT signaling in conjunction with Merlin and Expanded.";
RL Dev. Cell 18:288-299(2010).
RN [20]
RP INTERACTION WITH WWC1.
RX PubMed=20159599; DOI=10.1016/j.devcel.2009.12.011;
RA Genevet A., Wehr M.C., Brain R., Thompson B.J., Tapon N.;
RT "Kibra Is a regulator of the Salvador/Warts/Hippo signaling network.";
RL Dev. Cell 18:300-308(2010).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-313.
RX PubMed=11856822; DOI=10.1107/S0907444901021175;
RA Kang B.S., Cooper D.R., Devedjiev Y., Derewenda U., Derewenda Z.S.;
RT "The structure of the FERM domain of merlin, the neurofibromatosis
RT type 2 gene product.";
RL Acta Crystallogr. D 58:381-391(2002).
RN [23]
RP VARIANT NF2 TYR-220.
RX PubMed=8230593; DOI=10.1001/jama.270.19.2316;
RA Maccollin M.M., Mohney T., Trofatter J.A., Wertelecki W., Ramesh V.,
RA Gusella J.F.;
RT "DNA diagnosis of neurofibromatosis 2. Altered coding sequence of the
RT merlin tumor suppressor in an extended pedigree.";
RL JAMA 270:2316-2320(1993).
RN [24]
RP VARIANT NF2 PHE-96 DEL.
RX PubMed=7913580;
RA Maccollin M.M., Ramesh V., Jacoby L.B., Louis D.N., Rubio M.-P.,
RA Pulaski K., Trofatter J.A., Short M.P., Bove C., Eldridge R.,
RA Parry D.M., Gusella J.F.;
RT "Mutational analysis of patients with neurofibromatosis 2.";
RL Am. J. Hum. Genet. 55:314-320(1994).
RN [25]
RP VARIANT ARG-46.
RX PubMed=8004107; DOI=10.1093/hmg/3.2.347;
RA Irving R.M., Moffat D.A., Hardy D.G., Barton D.E., Xuereb J.H.,
RA Maher E.R.;
RT "Somatic NF2 gene mutations in familial and non-familial vestibular
RT schwannoma.";
RL Hum. Mol. Genet. 3:347-350(1994).
RN [26]
RP VARIANTS MET-219 AND CYS-418.
RX PubMed=8012353; DOI=10.1093/hmg/3.3.413;
RA Jacoby L.B., Maccollin M.M., Louis D.N., Mohney T., Rubio M.-P.,
RA Pulaski K., Trofatter J.A., Kley N., Seizinger B.R., Ramesh V.,
RA Gusella J.F.;
RT "Exon scanning for mutation of the NF2 gene in schwannomas.";
RL Hum. Mol. Genet. 3:413-419(1994).
RN [27]
RP VARIANTS NF2 SER-62; GLY-106 AND MET-352.
RX PubMed=8081368; DOI=10.1093/hmg/3.5.813;
RA Bourn D., Carter S.A., Mason S., Gareth D., Evans R., Strachan T.;
RT "Germline mutations in the neurofibromatosis type 2 tumour suppressor
RT gene.";
RL Hum. Mol. Genet. 3:813-816(1994).
RN [28]
RP VARIANTS GLU-79 AND HIS-351.
RX PubMed=7951231; DOI=10.1093/hmg/3.6.885;
RA Sainz J., Huynh D.P., Figueroa K., Ragge N.K., Baser M.E., Pulst S.M.;
RT "Mutations of the neurofibromatosis type 2 gene and lack of the gene
RT product in vestibular schwannomas.";
RL Hum. Mol. Genet. 3:885-891(1994).
RN [29]
RP VARIANTS PHE-273 AND ILE-364.
RX PubMed=8162073; DOI=10.1038/ng0294-185;
RA Bianchi A.B., Hara T., Ramesh V., Gao J., Klein Szanto A.J., Morin F.,
RA Menon A.G., Trofatter J.A., Gusella J.F., Seizinger B.R., Kley N.;
RT "Mutations in transcript isoforms of the neurofibromatosis 2 gene in
RT multiple human tumour types.";
RL Nat. Genet. 6:185-192(1994).
RN [30]
RP VARIANTS NF2 PHE-119 DEL; GLU-413 AND PRO-535.
RX PubMed=7759081; DOI=10.1007/BF00223872;
RA Bourn D., Evans G., Mason S., Tekes S., Trueman L., Strachan T.;
RT "Eleven novel mutations in the NF2 tumour suppressor gene.";
RL Hum. Genet. 95:572-574(1995).
RN [31]
RP VARIANT NF2 PRO-535.
RX PubMed=7666400;
RA Evans D.G.R., Bourn D., Wallace A., Ramsden R.T., Mitchell J.D.,
RA Strachan T.;
RT "Diagnostic issues in a family with late onset type 2
RT neurofibromatosis.";
RL J. Med. Genet. 32:470-474(1995).
RN [32]
RP VARIANT NF2 PRO-538.
RX PubMed=8566958; DOI=10.1007/BF02265270;
RA Kluwe L., Mautner V.-F.;
RT "A missense mutation in the NF2 gene results in moderate and mild
RT clinical phenotypes of neurofibromatosis type 2.";
RL Hum. Genet. 97:224-227(1996).
RN [33]
RP VARIANTS PHE-96 DEL; ILE-117; PHE-119 DEL; 122-VAL--GLU-129 DEL AND
RP PHE-339.
RX PubMed=8655144; DOI=10.1007/s004390050107;
RA de Vitis L.R., Tedde A., Vitelli F., Ammannati F., Mennonna P.,
RA Bigozzi U., Montali E., Papi L.;
RT "Screening for mutations in the neurofibromatosis type 2 (NF2) gene in
RT sporadic meningiomas.";
RL Hum. Genet. 97:632-637(1996).
RN [34]
RP VARIANTS NF2 CYS-197 AND HIS-539.
RX PubMed=8698340; DOI=10.1007/s004390050188;
RA Welling D.B., Guida M., Goll F., Pearl D.K., Glasscock M.E.,
RA Pappas D.G., Linthicum F.H., Rogers D., Prior T.W.;
RT "Mutational spectrum in the neurofibromatosis type 2 gene in sporadic
RT and familial schwannomas.";
RL Hum. Genet. 98:189-193(1996).
RN [35]
RP VARIANTS NF2 SER-62; VAL-77; GLY-106; MET-352; GLU-413 AND PRO-535.
RX PubMed=9643284;
RA Evans D.G.R., Trueman L., Wallace A., Collins S., Strachan T.;
RT "Genotype/phenotype correlations in type 2 neurofibromatosis (NF2):
RT evidence for more severe disease associated with truncating
RT mutations.";
RL J. Med. Genet. 35:450-455(1998).
RN [36]
RP ERRATUM.
RA Evans D.G., Trueman L., Wallace A., Collins S., Strachan T.;
RL J. Med. Genet. 36:87-87(1999).
RN [37]
RP VARIANT NF2 ARG-234.
RX PubMed=10090912; DOI=10.1086/302338;
RA Baser M.E., Kluwe L., Mautner V.-F.;
RT "Germ-line NF2 mutations and disease severity in neurofibromatosis
RT type 2 patients with retinal abnormalities.";
RL Am. J. Hum. Genet. 64:1230-1233(1999).
RN [38]
RP VARIANTS NF2 SER-62; THR-533 AND MET-579.
RX PubMed=10790209;
RX DOI=10.1002/(SICI)1098-1004(200005)15:5<474::AID-HUMU9>3.0.CO;2-7;
RA Faudoa R., Xue Z., Lee F., Baser M.E., Hung G.;
RT "Detection of novel NF2 mutations by an RNA mismatch cleavage
RT method.";
RL Hum. Mutat. 15:474-478(2000).
RN [39]
RP VARIANT NF2 PRO-141.
RX PubMed=12709270;
RA Verlinsky Y., Rechitsky S., Verlinsky O., Chistokhina A.,
RA Sharapova T., Masciangelo C., Levy M., Kaplan B., Lederer K.,
RA Kuliev A.;
RT "Preimplantation diagnosis for neurofibromatosis.";
RL Reprod. BioMed. Online 4:218-222(2002).
RN [40]
RP VARIANT [LARGE SCALE ANALYSIS] LYS-463.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [41]
RP INVOLVEMENT IN SCHWA.
RX PubMed=18072270; DOI=10.1002/humu.20679;
RA Sestini R., Bacci C., Provenzano A., Genuardi M., Papi L.;
RT "Evidence of a four-hit mechanism involving SMARCB1 and NF2 in
RT schwannomatosis-associated schwannomas.";
RL Hum. Mutat. 29:227-231(2008).
RN [42]
RP VARIANT NF2 ARG-133.
RX PubMed=20445339; DOI=10.3343/kjlm.2010.30.2.190;
RA Seong M.W., Yeo I.K., Cho S.I., Park C.K., Kim S.K., Paek S.H.,
RA Kim D.G., Jung H.W., Park H., Kim S.Y., Kim J.Y., Park S.S.;
RT "Molecular characterization of the NF2 gene in Korean patients with
RT neurofibromatosis type 2: a report of four novel mutations.";
RL Korean J. Lab. Med. 30:190-194(2010).
CC -!- FUNCTION: Probable regulator of the Hippo/SWH (Sav/Wts/Hpo)
CC signaling pathway, a signaling pathway that plays a pivotal role
CC in tumor suppression by restricting proliferation and promoting
CC apoptosis. Along with WWC1 can synergistically induce the
CC phosphorylation of LATS1 and LATS2 and can probably function in
CC the regulation of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway.
CC May act as a membrane stabilizing protein. May inhibit PI3 kinase
CC by binding to AGAP2 and impairing its stimulating activity.
CC Suppresses cell proliferation and tumorigenesis by inhibiting the
CC CUL4A-RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex.
CC -!- SUBUNIT: Interacts with SLC9A3R1, HGS and AGAP2. Interacts with
CC LAYN (By similarity). Interacts with SGSM3. Interacts (via FERM
CC domain) with MPP1. Interacts with WWC1. Interacts with the CUL4A-
CC RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex. The
CC unphosphorylated form interacts (via FERM domain) with
CC VPRBP/DCAF1.
CC -!- INTERACTION:
CC Q4VCS5:AMOT; NbExp=7; IntAct=EBI-1014472, EBI-2511319;
CC Q4VCS5-1:AMOT; NbExp=2; IntAct=EBI-1014472, EBI-3903812;
CC Q4VCS5-2:AMOT; NbExp=6; IntAct=EBI-1014472, EBI-3891843;
CC Q9BZE4:GTPBP4; NbExp=9; IntAct=EBI-1014472, EBI-1056249;
CC Q8NI35:INADL; NbExp=2; IntAct=EBI-1014472, EBI-724390;
CC Q16584:MAP3K11; NbExp=4; IntAct=EBI-1014472, EBI-49961;
CC Q9H204:MED28; NbExp=4; IntAct=EBI-1014472, EBI-514199;
CC Q10728:Ppp1r12a (xeno); NbExp=2; IntAct=EBI-1014472, EBI-918263;
CC Q3TI53:Schip1 (xeno); NbExp=2; IntAct=EBI-1014472, EBI-1397475;
CC O14745:SLC9A3R1; NbExp=4; IntAct=EBI-1014500, EBI-349787;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell projection, filopodium
CC membrane; Peripheral membrane protein; Cytoplasmic side. Cell
CC projection, ruffle membrane; Peripheral membrane protein;
CC Cytoplasmic side. Nucleus. Note=In a fibroblastic cell line,
CC isoform 1 is found homogeneously distributed over the entire cell,
CC with a particularly strong staining in ruffling membranes and
CC filopodia. Colocalizes with MPP1 in non-myelin-forming Schwann
CC cells. Binds with VPRBP in the nucleus. The intramolecular
CC association of the FERM domain with the C-terminal tail promotes
CC nuclear accumulation. The unphosphorylated form accumulates
CC predominantly in the nucleus while the phosphorylated form is
CC largely confined to the non-nuclear fractions.
CC -!- SUBCELLULAR LOCATION: Isoform 7: Cytoplasm, perinuclear region.
CC Cytoplasmic granule. Note=Observed in cytoplasmic granules
CC concentrated in a perinuclear location. Isoform 7 is absent from
CC ruffling membranes and filopodia.
CC -!- SUBCELLULAR LOCATION: Isoform 9: Cytoplasm, perinuclear region.
CC Cytoplasmic granule. Note=Observed in cytoplasmic granules
CC concentrated in a perinuclear location. Isoform 9 is absent from
CC ruffling membranes and filopodia.
CC -!- SUBCELLULAR LOCATION: Isoform 10: Nucleus. Cell projection,
CC filopodium membrane; Peripheral membrane protein; Cytoplasmic
CC side. Cell projection, ruffle membrane; Peripheral membrane
CC protein; Cytoplasmic side. Cytoplasm, perinuclear region.
CC Cytoplasmic granule. Cytoplasm, cytoskeleton. Note=In a
CC fibroblastic cell line, isoform 10 is found homogeneously
CC distributed over the entire cell, with a particularly strong
CC staining in ruffling membranes and filopodia.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=10;
CC Name=1; Synonyms=I;
CC IsoId=P35240-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P35240-2; Sequence=VSP_000492;
CC Name=3; Synonyms=II;
CC IsoId=P35240-3; Sequence=VSP_007050, VSP_007051;
CC Name=4; Synonyms=delE2/3;
CC IsoId=P35240-4; Sequence=VSP_007041, VSP_007050, VSP_007051;
CC Name=5; Synonyms=delE3;
CC IsoId=P35240-5; Sequence=VSP_007042, VSP_007050, VSP_007051;
CC Name=6; Synonyms=delE2;
CC IsoId=P35240-6; Sequence=VSP_007040, VSP_007050, VSP_007051;
CC Name=7; Synonyms=MER150;
CC IsoId=P35240-7; Sequence=VSP_007045, VSP_007046;
CC Name=8;
CC IsoId=P35240-8; Sequence=VSP_007048, VSP_007050, VSP_007051;
CC Name=9; Synonyms=MER162;
CC IsoId=P35240-9; Sequence=VSP_007044;
CC Name=10; Synonyms=MER151;
CC IsoId=P35240-10; Sequence=VSP_007041, VSP_007043, VSP_007047,
CC VSP_007049;
CC -!- TISSUE SPECIFICITY: Widely expressed. Isoform 1 and isoform 3 are
CC predominant. Isoform 4, isoform 5 and isoform 6 are expressed
CC moderately. Isoform 8 is found at low frequency. Isoform 7,
CC isoform 9 and isoform 10 are not expressed in adult tissues, with
CC the exception of adult retina expressing isoform 10. Isoform 9 is
CC faintly expressed in fetal brain, heart, lung, skeletal muscle and
CC spleen. Fetal thymus expresses isoforms 1, 7, 9 and 10 at similar
CC levels.
CC -!- PTM: Phosphorylation of Ser-518 inhibits nuclear localization by
CC disrupting the intramolecular association of the FERM domain with
CC the C-terminal tail.
CC -!- PTM: Ubiquitinated by the CUL4A-RBX1-DDB1-DCAF1/VprBP E3
CC ubiquitin-protein ligase complex for ubiquitination and subsequent
CC proteasome-dependent degradation.
CC -!- DISEASE: Neurofibromatosis 2 (NF2) [MIM:101000]: Genetic disorder
CC characterized by bilateral vestibular schwannomas (formerly called
CC acoustic neuromas), schwannomas of other cranial and peripheral
CC nerves, meningiomas, and ependymomas. It is inherited in an
CC autosomal dominant fashion with full penetrance. Affected
CC individuals generally develop symptoms of eighth-nerve dysfunction
CC in early adulthood, including deafness and balance disorder.
CC Although the tumors of NF2 are histologically benign, their
CC anatomic location makes management difficult, and patients suffer
CC great morbidity and mortality. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Schwannomatosis (SCHWA) [MIM:162091]: Schwannomas are
CC benign tumors of the peripheral nerve sheath that usually occur
CC singly in otherwise normal individuals. Multiple schwannomas in
CC the same individual suggest an underlying tumor-predisposition
CC syndrome. The most common such syndrome is NF2. The hallmark of
CC NF2 is the development of bilateral vestibular-nerve schwannomas;
CC but two-thirds or more of all NF2-affected individuals develop
CC schwannomas in other locations, and dermal schwannomas may precede
CC vestibular tumors in NF2-affected children. There have been
CC several reports of individuals with multiple schwannomas who do
CC not show evidence of vestibular schwannoma. Clinical report
CC suggests that schwannomatosis is a clinical entity distinct from
CC other forms of neurofibromatosis. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Mesothelioma, malignant (MESOM) [MIM:156240]: An
CC aggressive neoplasm of the serosal lining of the chest. It appears
CC as broad sheets of cells, with some regions containing spindle-
CC shaped, sarcoma-like cells and other regions showing adenomatous
CC patterns. Pleural mesotheliomas have been linked to exposure to
CC asbestos. Note=The disease may be caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 FERM domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/NF2117.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NF2";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; L11353; AAA36212.1; -; mRNA.
DR EMBL; X72655; CAA51220.1; -; Genomic_DNA.
DR EMBL; X72656; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72657; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72658; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72659; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72660; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72661; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72662; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72663; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72664; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72665; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72666; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72667; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72668; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72669; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; X72670; CAA51220.1; JOINED; Genomic_DNA.
DR EMBL; Z22664; CAA80377.1; -; mRNA.
DR EMBL; Y18000; CAA76992.1; -; Genomic_DNA.
DR EMBL; Y18000; CAA76993.1; -; Genomic_DNA.
DR EMBL; AF122827; AAD48752.1; -; mRNA.
DR EMBL; AF122828; AAD48753.1; -; mRNA.
DR EMBL; AF123570; AAD48754.1; -; mRNA.
DR EMBL; AF369657; AAK54160.1; -; mRNA.
DR EMBL; AF369658; AAK54161.1; -; mRNA.
DR EMBL; AF369661; AAK54162.1; -; mRNA.
DR EMBL; AF369662; AAK54163.1; -; mRNA.
DR EMBL; AF369663; AAK54164.1; -; mRNA.
DR EMBL; AF369664; AAK54165.1; -; mRNA.
DR EMBL; AF369665; AAK54166.1; -; mRNA.
DR EMBL; AF369700; AAK54195.1; -; mRNA.
DR EMBL; AF369701; AAK54196.1; -; mRNA.
DR EMBL; CR456530; CAG30416.1; -; mRNA.
DR EMBL; BC003112; AAH03112.2; -; mRNA.
DR EMBL; BC020257; AAH20257.1; -; mRNA.
DR PIR; S33809; S33809.
DR RefSeq; NP_000259.1; NM_000268.3.
DR RefSeq; NP_057502.2; NM_016418.5.
DR RefSeq; NP_861546.1; NM_181825.2.
DR RefSeq; NP_861966.1; NM_181828.2.
DR RefSeq; NP_861967.1; NM_181829.2.
DR RefSeq; NP_861968.1; NM_181830.2.
DR RefSeq; NP_861969.1; NM_181831.2.
DR RefSeq; NP_861970.1; NM_181832.2.
DR RefSeq; NP_861971.1; NM_181833.2.
DR UniGene; Hs.187898; -.
DR PDB; 1H4R; X-ray; 1.80 A; A/B=1-313.
DR PDB; 3U8Z; X-ray; 2.64 A; A/B/C/D=18-312.
DR PDBsum; 1H4R; -.
DR PDBsum; 3U8Z; -.
DR ProteinModelPortal; P35240; -.
DR SMR; P35240; 18-382.
DR IntAct; P35240; 18.
DR PhosphoSite; P35240; -.
DR DMDM; 462594; -.
DR PaxDb; P35240; -.
DR PRIDE; P35240; -.
DR DNASU; 4771; -.
DR Ensembl; ENST00000334961; ENSP00000335652; ENSG00000186575.
DR Ensembl; ENST00000338641; ENSP00000344666; ENSG00000186575.
DR Ensembl; ENST00000347330; ENSP00000335160; ENSG00000186575.
DR Ensembl; ENST00000353887; ENSP00000340626; ENSG00000186575.
DR Ensembl; ENST00000361166; ENSP00000354529; ENSG00000186575.
DR Ensembl; ENST00000361452; ENSP00000354897; ENSG00000186575.
DR Ensembl; ENST00000361676; ENSP00000355183; ENSG00000186575.
DR Ensembl; ENST00000397789; ENSP00000380891; ENSG00000186575.
DR Ensembl; ENST00000403435; ENSP00000384029; ENSG00000186575.
DR Ensembl; ENST00000403999; ENSP00000384797; ENSG00000186575.
DR Ensembl; ENST00000413209; ENSP00000409921; ENSG00000186575.
DR Ensembl; ENST00000432151; ENSP00000395885; ENSG00000186575.
DR GeneID; 4771; -.
DR KEGG; hsa:4771; -.
DR UCSC; uc003age.4; human.
DR CTD; 4771; -.
DR GeneCards; GC22P029999; -.
DR HGNC; HGNC:7773; NF2.
DR HPA; CAB005385; -.
DR HPA; HPA003097; -.
DR MIM; 101000; phenotype.
DR MIM; 156240; phenotype.
DR MIM; 162091; phenotype.
DR MIM; 607379; gene.
DR neXtProt; NX_P35240; -.
DR Orphanet; 637; Neurofibromatosis type 2.
DR Orphanet; 93921; Neurofibromatosis type 3.
DR PharmGKB; PA31580; -.
DR eggNOG; NOG328202; -.
DR HOVERGEN; HBG002185; -.
DR InParanoid; P35240; -.
DR KO; K16684; -.
DR OMA; ITNEMER; -.
DR OrthoDB; EOG7BGHK6; -.
DR SignaLink; P35240; -.
DR EvolutionaryTrace; P35240; -.
DR GeneWiki; Merlin_(protein); -.
DR GenomeRNAi; 4771; -.
DR NextBio; 18368; -.
DR PMAP-CutDB; P35240; -.
DR PRO; PR:P35240; -.
DR ArrayExpress; P35240; -.
DR Bgee; P35240; -.
DR Genevestigator; P35240; -.
DR GO; GO:0005912; C:adherens junction; IEA:Ensembl.
DR GO; GO:0032154; C:cleavage furrow; IEA:Ensembl.
DR GO; GO:0030864; C:cortical actin cytoskeleton; IEA:Ensembl.
DR GO; GO:0005856; C:cytoskeleton; TAS:ProtInc.
DR GO; GO:0005769; C:early endosome; IDA:HGNC.
DR GO; GO:0019898; C:extrinsic to membrane; IEA:InterPro.
DR GO; GO:0031527; C:filopodium membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030027; C:lamellipodium; IEA:Ensembl.
DR GO; GO:0005730; C:nucleolus; IDA:HGNC.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:HGNC.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030036; P:actin cytoskeleton organization; IMP:HGNC.
DR GO; GO:0045216; P:cell-cell junction organization; IEA:Ensembl.
DR GO; GO:0007398; P:ectoderm development; IEA:Ensembl.
DR GO; GO:0070306; P:lens fiber cell differentiation; IEA:Ensembl.
DR GO; GO:0001707; P:mesoderm formation; IEA:Ensembl.
DR GO; GO:0030336; P:negative regulation of cell migration; TAS:HGNC.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0022408; P:negative regulation of cell-cell adhesion; IDA:HGNC.
DR GO; GO:0001953; P:negative regulation of cell-matrix adhesion; TAS:HGNC.
DR GO; GO:0008156; P:negative regulation of DNA replication; IMP:HGNC.
DR GO; GO:0043409; P:negative regulation of MAPK cascade; IEA:Ensembl.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IEA:Ensembl.
DR GO; GO:0042518; P:negative regulation of tyrosine phosphorylation of Stat3 protein; IDA:HGNC.
DR GO; GO:0042524; P:negative regulation of tyrosine phosphorylation of Stat5 protein; IDA:HGNC.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR GO; GO:0051496; P:positive regulation of stress fiber assembly; IMP:HGNC.
DR GO; GO:0035330; P:regulation of hippo signaling cascade; IMP:UniProtKB.
DR GO; GO:0014010; P:Schwann cell proliferation; IMP:HGNC.
DR Gene3D; 1.20.80.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR019750; Band_41_fam.
DR InterPro; IPR015788; EMR2/Merlin.
DR InterPro; IPR011174; ERM.
DR InterPro; IPR011259; ERM_C_dom.
DR InterPro; IPR000798; Ez/rad/moesin_like.
DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_3-hlx.
DR InterPro; IPR019748; FERM_central.
DR InterPro; IPR019747; FERM_CS.
DR InterPro; IPR000299; FERM_domain.
DR InterPro; IPR018979; FERM_N.
DR InterPro; IPR018980; FERM_PH-like_C.
DR InterPro; IPR008954; Moesin_tail.
DR InterPro; IPR011993; PH_like_dom.
DR PANTHER; PTHR23281:SF4; PTHR23281:SF4; 1.
DR Pfam; PF00769; ERM; 1.
DR Pfam; PF09380; FERM_C; 1.
DR Pfam; PF00373; FERM_M; 1.
DR Pfam; PF09379; FERM_N; 1.
DR PIRSF; PIRSF002305; ERM; 1.
DR PRINTS; PR00935; BAND41.
DR PRINTS; PR00661; ERMFAMILY.
DR SMART; SM00295; B41; 1.
DR SUPFAM; SSF47031; SSF47031; 1.
DR SUPFAM; SSF48678; SSF48678; 1.
DR PROSITE; PS00660; FERM_1; 1.
DR PROSITE; PS00661; FERM_2; 1.
DR PROSITE; PS50057; FERM_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cell projection;
KW Complete proteome; Cytoplasm; Cytoskeleton; Deafness;
KW Disease mutation; Membrane; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Tumor suppressor; Ubl conjugation.
FT CHAIN 1 595 Merlin.
FT /FTId=PRO_0000219412.
FT DOMAIN 22 311 FERM.
FT COMPBIAS 327 465 Glu-rich.
FT MOD_RES 518 518 Phosphoserine; by PAK.
FT VAR_SEQ 39 121 Missing (in isoform 4 and isoform 10).
FT /FTId=VSP_007041.
FT VAR_SEQ 39 80 Missing (in isoform 6).
FT /FTId=VSP_007040.
FT VAR_SEQ 81 121 Missing (in isoform 5).
FT /FTId=VSP_007042.
FT VAR_SEQ 150 579 Missing (in isoform 9).
FT /FTId=VSP_007044.
FT VAR_SEQ 150 225 Missing (in isoform 10).
FT /FTId=VSP_007043.
FT VAR_SEQ 259 259 N -> R (in isoform 7).
FT /FTId=VSP_007045.
FT VAR_SEQ 260 595 Missing (in isoform 7).
FT /FTId=VSP_007046.
FT VAR_SEQ 334 379 MERQRLAREKQMREEAERTRDELERRLLQMKEEATMANEAL
FT MRSEE -> GQRGRSAEAGPAGSTRGGAKSQAEAPGDCHQA
FT HVPAHEPNSSTVAS (in isoform 10).
FT /FTId=VSP_007047.
FT VAR_SEQ 335 363 Missing (in isoform 8).
FT /FTId=VSP_007048.
FT VAR_SEQ 380 595 Missing (in isoform 10).
FT /FTId=VSP_007049.
FT VAR_SEQ 580 595 LTLQSAKSRVAFFEEL -> SSPRQKTYLHLSPQSRLFPGT
FT LYVVMLYVVMVLPSVILTRA (in isoform 2).
FT /FTId=VSP_000492.
FT VAR_SEQ 580 590 LTLQSAKSRVA -> PQAQGRRPICI (in isoform 3,
FT isoform 4, isoform 5, isoform 6 and
FT isoform 8).
FT /FTId=VSP_007050.
FT VAR_SEQ 591 595 Missing (in isoform 3, isoform 4, isoform
FT 5, isoform 6 and isoform 8).
FT /FTId=VSP_007051.
FT VARIANT 46 46 L -> R (in vestibular schwannoma; loss of
FT ability to interact with the CUL4A-RBX1-
FT DDB1-VprBP/DCAF1 E3 ubiquitin-protein
FT ligase complex).
FT /FTId=VAR_000809.
FT VARIANT 62 62 F -> S (in NF2; loss of ability to
FT interact with the CUL4A-RBX1-DDB1-VprBP/
FT DCAF1 E3 ubiquitin-protein ligase
FT complex).
FT /FTId=VAR_000810.
FT VARIANT 77 77 M -> V (in NF2).
FT /FTId=VAR_043011.
FT VARIANT 79 79 K -> E (in vestibular schwannoma).
FT /FTId=VAR_000811.
FT VARIANT 96 96 Missing (in NF2 and in sporadic
FT meningioma).
FT /FTId=VAR_000812.
FT VARIANT 106 106 E -> G (in NF2).
FT /FTId=VAR_000813.
FT VARIANT 117 117 L -> I (in sporadic meningioma).
FT /FTId=VAR_000814.
FT VARIANT 119 119 Missing (in sporadic meningioma).
FT /FTId=VAR_000815.
FT VARIANT 122 129 Missing (in sporadic meningioma).
FT /FTId=VAR_000816.
FT VARIANT 133 133 C -> R (in NF2).
FT /FTId=VAR_065227.
FT VARIANT 141 141 L -> P (in NF2; loss of ability to
FT interact with the CUL4A-RBX1-DDB1-VprBP/
FT DCAF1 E3 ubiquitin-protein ligase
FT complex).
FT /FTId=VAR_043012.
FT VARIANT 197 197 G -> C (in NF2).
FT /FTId=VAR_043013.
FT VARIANT 219 219 V -> M (in vestibular schwannoma).
FT /FTId=VAR_000817.
FT VARIANT 220 220 N -> Y (in NF2).
FT /FTId=VAR_000818.
FT VARIANT 234 234 L -> R (in NF2 and in retinal hamartoma;
FT severe).
FT /FTId=VAR_009123.
FT VARIANT 273 273 I -> F (in breast ductal carcinoma).
FT /FTId=VAR_000819.
FT VARIANT 339 339 L -> F (in sporadic meningioma).
FT /FTId=VAR_000820.
FT VARIANT 344 344 Q -> H (in dbSNP:rs2229064).
FT /FTId=VAR_048358.
FT VARIANT 351 351 R -> H.
FT /FTId=VAR_029041.
FT VARIANT 352 352 T -> M (in NF2).
FT /FTId=VAR_000821.
FT VARIANT 360 360 L -> P (in NF2).
FT /FTId=VAR_000822.
FT VARIANT 364 364 K -> I (in melanoma).
FT /FTId=VAR_000823.
FT VARIANT 413 413 K -> E (in NF2).
FT /FTId=VAR_043014.
FT VARIANT 418 418 R -> C (in vestibular schwannoma).
FT /FTId=VAR_000824.
FT VARIANT 463 463 E -> K (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035848.
FT VARIANT 533 533 K -> T (in NF2).
FT /FTId=VAR_043015.
FT VARIANT 535 535 L -> P (in NF2; late onset).
FT /FTId=VAR_000825.
FT VARIANT 538 538 Q -> P (in NF2; mild).
FT /FTId=VAR_000826.
FT VARIANT 539 539 L -> H (in NF2).
FT /FTId=VAR_043016.
FT VARIANT 579 579 K -> M (in NF2).
FT /FTId=VAR_043017.
FT MUTAGEN 64 64 L->P: Abolishes binding to AGAP2 and
FT interaction with the CUL4A-RBX1-DDB1-
FT VprBP/DCAF1 E3 ubiquitin-protein ligase
FT complex.
FT MUTAGEN 518 518 S->A: Loss of phosphorylation.
FT Significant accumulation in the nucleus
FT and no effect on binding to VPRBP.
FT MUTAGEN 518 518 S->D: No effect on phosphorylation.
FT Defective nuclear accumulation.
FT Significant decrease in binding to VPRBP
FT and in ability to inhibit cell
FT proliferation.
FT CONFLICT 77 77 M -> I (in Ref. 7; AAH20257).
FT CONFLICT 581 581 T -> P (in Ref. 5; AAK54160/AAK54162).
FT STRAND 21 27
FT STRAND 32 38
FT HELIX 43 54
FT HELIX 59 61
FT STRAND 62 68
FT STRAND 71 74
FT STRAND 77 80
FT HELIX 81 83
FT STRAND 89 100
FT HELIX 105 108
FT HELIX 112 127
FT HELIX 135 150
FT TURN 155 157
FT TURN 160 165
FT HELIX 171 174
FT HELIX 181 193
FT TURN 194 197
FT HELIX 200 211
FT TURN 215 218
FT STRAND 220 226
FT STRAND 231 236
FT STRAND 238 244
FT STRAND 249 251
FT STRAND 253 257
FT HELIX 258 260
FT STRAND 261 267
FT STRAND 270 277
FT STRAND 283 286
FT HELIX 290 310
SQ SEQUENCE 595 AA; 69690 MW; B1A1BF2BD5DA561C CRC64;
MAGAIASRMS FSSLKRKQPK TFTVRIVTMD AEMEFNCEMK WKGKDLFDLV CRTLGLRETW
FFGLQYTIKD TVAWLKMDKK VLDHDVSKEE PVTFHFLAKF YPENAEEELV QEITQHLFFL
QVKKQILDEK IYCPPEASVL LASYAVQAKY GDYDPSVHKR GFLAQEELLP KRVINLYQMT
PEMWEERITA WYAEHRGRAR DEAEMEYLKI AQDLEMYGVN YFAIRNKKGT ELLLGVDALG
LHIYDPENRL TPKISFPWNE IRNISYSDKE FTIKPLDKKI DVFKFNSSKL RVNKLILQLC
IGNHDLFMRR RKADSLEVQQ MKAQAREEKA RKQMERQRLA REKQMREEAE RTRDELERRL
LQMKEEATMA NEALMRSEET ADLLAEKAQI TEEEAKLLAQ KAAEAEQEMQ RIKATAIRTE
EEKRLMEQKV LEAEVLALKM AEESERRAKE ADQLKQDLQE AREAERRAKQ KLLEIATKPT
YPPMNPIPAP LPPDIPSFNL IGDSLSFDFK DTDMKRLSME IEKEKVEYME KSKHLQEQLN
ELKTEIEALK LKERETALDI LHNENSDRGG SSKHNTIKKL TLQSAKSRVA FFEEL
//

MIM 101000
*RECORD*
*FIELD* NO
101000
*FIELD* TI
#101000 NEUROFIBROMATOSIS, TYPE II; NF2
;;NEUROFIBROMATOSIS, CENTRAL TYPE;;
ACOUSTIC SCHWANNOMAS, BILATERAL;;
read moreBILATERAL ACOUSTIC NEUROFIBROMATOSIS; BANF;;
ACOUSTIC NEURINOMA, BILATERAL; ACN
*FIELD* TX
A number sign (#) is used with this entry because neurofibromatosis type
II is caused by mutation in the gene encoding neurofibromin-2 (NF2;
607379), which is also called merlin, on chromosome 22q12.2.

DESCRIPTION

The central or type II form of neurofibromatosis (NF2) is an autosomal
dominant multiple neoplasia syndrome characterized by tumors of the
eighth cranial nerve (usually bilateral), meningiomas of the brain, and
schwannomas of the dorsal roots of the spinal cord. The incidence of
neurofibromatosis type II is 1 in 25,000 live births (Asthagiri et al.,
2009). NF2 has few of the hallmarks of the peripheral or type I form of
neurofibromatosis (NF1; 162200), also known as von Recklinghausen
disease.

Asthagiri et al. (2009) provided a detailed review of neurofibromatosis
type II.

CLINICAL FEATURES

Gardner and Frazier (1933) reported a family of 5 generations in which
38 members were deaf because of bilateral acoustic neuromas; of these,
15 later became blind. The average age at onset of deafness was 20
years. The average age at death of affected persons in the second
generation was 72, in the third generation 63, in the fourth 42, and in
the fifth 28. Follow-up of this family (Gardner and Turner, 1940; Young
et al., 1970) revealed no evidence of the systemic manifestations of
neurofibromatosis I (NF1; 162200), also known as von Recklinghausen
disease. Other families with no evidence of the latter disease were
reported by Worster-Drought et al. (1937), Feiling and Ward (1920), and
Moyes (1968). Worster-Drought et al. (1937) pointed out that Wishart
(1822) was the first to report a case of bilateral acoustic neuroma.
Wishart's patient, Michael Blair, was 21 years old when he consulted Mr.
Wishart, president of the Royal College of Surgeons of Edinburgh,
because of bilateral deafness. He had a peculiarly shaped head from
infancy, and blindness in the right eye was discovered at about 4 months
after birth. He became completely blind and deaf toward the end of his
life. Autopsy revealed tumors of the dura mater and brain and also a
'tumour of the size of a small nut, and very hard, being attached to
each of them (auditory nerves), just where they enter the meatus
auditorius internus.'

Nager (1969) showed that in about 4% of cases acoustic neuroma is
bilateral. In addition to their autosomal dominant inheritance and
association with neurofibromatosis, bilateral tumors differ from
unilateral ones in that they can reach a remarkably large size with
extensive involvement of the temporal bone and the nerves therein.
Fabricant et al. (1979) reported that more than 30 kindreds with
'central neurofibromatosis' had been described. Most patients with the
central form (NF2) have no cafe-au-lait spots or peripheral
neurofibromata, and no patients in one large series had 6 or more
cafe-au-lait spots (Eldridge, 1981).

Kanter et al. (1980), who reviewed 9 personally studied kindreds and 15
reported ones, with a total of 130 cases, showed an increase only in
antigenic activity of nerve growth factor (NGF; 162030) in central
neurofibromatosis and only in functional activity in peripheral
neurofibromatosis.

In a series reported by Mrazek et al. (1988), 1 of 41 acoustic neurinoma
cases was bilateral. This was in a 10-year-old girl with von
Recklinghausen neurofibromatosis, whose first tumor had been diagnosed
at age 6.

Mayfrank et al. (1990) studied 10 patients with NF2 and found that all
were sporadic cases, each presumably the result of a new mutational
event. From a survey of these patients and those in the literature, they
concluded that sporadic cases are characterized by a high incidence of
multiple meningiomas and spinal tumors in addition to bilateral acoustic
neurinomas.

Pulst et al. (1991) described a family with spinal neurofibromatosis
without cafe-au-lait spots or other manifestations of either NF1 or NF2
such as cutaneous tumors, Lisch nodules, or acoustic tumors. Mutation at
the NF1 locus was excluded with odds greater than 100,000:1. Markers
with the NF2 locus were uninformative in this family.

Evans et al. (1992, 1992) studied 150 patients. The mean age at onset
was 21.57 years (n = 110) and no patient presented after 55 years of
age. Patients presented with symptoms attributable to vestibular
schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumors.
In 100 patients studied personally by the authors, 44 presented with
deafness, which was unilateral in 35. Deafness was accompanied by
tinnitus in 10. Muscle weakness or wasting was the first symptom in 12%.
In 3 of the 100 patients, there was a distal symmetrical sensorimotor
neuropathy, confirmed by nerve conduction studies and electromyography.
Although similar features may result from the multiple spinal and
intracranial tumors that occur in this condition, a generalized and
isolated neuropathy appears to be a relatively common feature of NF2.
Cafe-au-lait spots occurred in 43 of the 100 patients but only 1 had as
many as 6 spots. Cataract was detected in 34 of 90 patients. Cataracts
were probably congenital in 4 patients in this study. Three types of
skin tumors were recognized. The first and least common was similar to
the intradermal papillary skin neurofibroma with violaceous coloring
occurring in NF1. The second type comprised subcutaneous
well-circumscribed, often spherical, tumors that appeared to be located
on peripheral nerves; the thickened nerve could often be palpated at
either end of the tumor, the skin being mobile and separate from the
tumor. The third and most frequent type, first described by Martuza and
Eldridge (1988), was represented by discrete well-circumscribed,
slightly raised, roughened areas of skin often pigmented and accompanied
by excess hair. Skin tumors of some kind were found in 68% of patients,
type 1 being present in 20%, type 2 in 33%, and type 3 in 47%. They
could find no evidence that either pregnancy or contraceptive pills has
adverse effects on vestibular schwannomas or other manifestations. Evans
et al. (1992) provided useful advice on the follow-up of persons
identified as having NF2 and the management of persons at risk of
developing NF2.

Evans et al. (1992) divided their 120 cases of NF2 into 2 types: the
Wishart (1822) type, with early onset, rapid course, and multiple other
tumors in addition to bilateral vestibular schwannomas, and the Gardner
type (1930, 1933, 1940), with late onset, more benign course, and
usually only bilateral vestibular schwannomas. This classification had
been suggested by Eldridge et al. (1991). Evans et al. (1992) found no
evidence for the existence of a third type of generalized
meningiomatosis that might be designated the Lee-Abbott type (Lee and
Abbott, 1969). The age at onset of deafness and the age at diagnosis
were almost identical in the 2 sexes. Birth incidence of NF2 was
estimated to be 1 in 33,000-40,562. Evans et al. (1992) considered 49%
of the 150 cases to represent new mutations. The mutation rate was
estimated to be 6.5 x 10(-6). A maternal effect on severity was noted in
that age of onset was 18.17 years in 36 maternally inherited cases and
24.5 years in 20 paternally inherited cases (p = 0.027). A preponderance
of maternally inherited cases was also significant (p = 0.03). (A
maternal effect on severity had been noted also for NF1.) Baser et al.
(2001) studied 140 patients and found that maternal inheritance was not
an independent correlate of NF2 disease severity.

Parry et al. (1994) assessed possible heterogeneity in NF2 by evaluating
63 affected members of 32 families. In addition to skin and neurologic
examinations, workup included audiometry, complete ophthalmologic
examination with slit-lamp biomicroscopy of the lens and fundus, and
gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean
age-at-onset in 58 individuals was 20.3 years; initial symptoms were
related to vestibular schwannomas (44.4%), other CNS tumors (22.2%),
skin tumors (12.7%), and ocular manifestations including cataracts and
retinal hamartomas (12.7%). Screening uncovered 5 affected but
asymptomatic family members; vestibular schwannomas were demonstrated in
62 (98.4%). Other findings included cataracts (81.0%), skin tumors
(67.7%), spinal tumors (67.4%), and meningiomas (49.2%). As a rule,
clinical manifestations and clinical course were similar within families
but differed among families. Parry et al. (1994) concluded that 2
subtypes but not 3 can be defined.

Evans et al. (1999) studied the presentation of NF2 in childhood. A
total of 334 cases of NF2 were identified from a comprehensive UK
dataset, of which 61 (18%) had presented in childhood (0-15 years).
Twenty-six of these children presented with symptoms of vestibular
schwannoma, 19 with meningioma, 7 with a spinal tumor, and 5 with a
cutaneous tumor. In addition, Evans et al. (1999) identified 22 children
with a meningioma from the Manchester Children's Tumor Registry, a
prospective database of children presenting with a tumor since 1954
within a defined population. At least 3 of these children subsequently
developed classic NF2, and in none of them was there a family history
suggestive of NF2. The authors concluded that NF2 should be considered
in any child presenting with meningioma, vestibular schwannoma, or
cutaneous symptoms such as neurofibroma or schwannoma, especially if
they have fewer than 6 cafe-au-lait patches and therefore do not fulfill
the diagnostic criteria for NF1.

Gijtenbeek et al. (2001) reported a patient with NF2, confirmed by
genetic analysis, who presented with an axonal mononeuropathy multiplex
with progression of axonal loss over several years. Sural nerve biopsy
showed small scattered groups of Schwann cells transformed into
irregular branching cells with abnormal cell-cell contacts. The authors
hypothesized that defective Schwann cell function, due to inactivation
of the NF2 gene product merlin, leads to changes in morphology,
cell-cell contact, and growth, and finally to degeneration of axons.

Egan et al. (2001) reported 4 cases of NF2 with a monocular elevator
paresis. Two of the patients had third nerve tumors demonstrable on MRI,
which had not been present on earlier films. The other 2 patients may
have had tumors too small for radiographic detection. The authors
suggested that the isolated paresis may result from compression of
particular fascicles of the third nerve that subserve the superior
rectus and inferior oblique muscles as they exit the midbrain, and noted
that ocular mobility defects should be closely monitored in patients
with NF2.

To evaluate clinical and molecular predictors of the risk of mortality
in persons with NF2, Baser et al. (2002) analyzed the mortality
experience of 368 patients from 261 families in the United Kingdom NF2
registry. Age at diagnosis, intracranial meningiomas, and type of
treatment center were informative predictors of the risk of mortality.
The relative risk of mortality increased 1.13-fold per year decrease in
age at diagnosis and was 2.51-fold greater in people with meningiomas
compared with those without meningiomas. The relative risk of mortality
in patients treated at specialty centers was 0.34, compared with those
treated at nonspecialty centers. The relative risk of mortality in
people with constitutional NF2 missense mutations was very low compared
with those with other types of mutations (nonsense, frameshift, or
splice site mutations, and large deletions), but the confidence interval
could not be quantified because there was only 1 death among people with
missense mutations.

- Ocular Abnormalities

Pearson-Webb et al. (1986) pointed out that Lisch nodules, which are
iris hamartomas that are frequently found in NF1, are not found in NF2.
They found, however, an apparently high frequency of presenile posterior
subcapsular and nuclear cataracts which sometimes required surgery
and/or predated the symptoms of bilateral acoustic neurofibromatosis.
Landau et al. (1990) described combined pigment epithelial and retinal
hamartoma (CEPRH) in NF2.

Kaiser-Kupfer et al. (1989) found posterior capsular lens opacities in
20 NF2 patients in 11 families. Parry et al. (1991) extended these
observations. In 26 persons who were first-degree relatives of an
affected individual, they found posterior capsular cataracts in 21. Of
14 at-risk individuals, i.e., persons with mild changes of NF but not
NF1, persons under age 40 with unilateral acoustic neuroma, a child with
meningioma and/or schwannoma, and a person with multiple meningioma,
they found posterior capsular lens opacities in 13. These patients
probably represented new mutations. The presence of posterior capsular
opacities in a relative of persons with NF2 was suggestive of NF2.
Furthermore, NF2 should be considered in young persons without NF1 but
with mild skin findings of NF or CNS tumors with posterior capsular
opacities. Bouzas et al. (1993) found posterior subcapsular/capsular
cataracts in 36 (80%) of 45 affected individuals in 29 families. In
addition, the association of peripheral cortical lens opacities with NF2
was found to be statistically significant: such cataracts were found in
17 of the patients (37.8%) but in none of the unaffected family members
(p less than 0.0001). In 3 patients, peripheral cortical opacities were
present despite the absence of posterior subcapsular/capsular cataracts.
Bouzas et al. (1993), reporting further on the NIH experience, reviewed
visual impairment in 54 NF2 patients, 51 of whom had bilateral
vestibular schwannomas. Causes of decreased vision were cataracts,
damage in the optic pathways, macular hamartomas, and corneal opacities.
Although lens opacities are an important marker for NF2, they usually do
not interfere with vision; some progress, requiring cataract extraction.
In 6 patients, decreased visual acuity was due to corneal opacifications
secondary to either seventh or fifth cranial nerve damage, or both.
Damage to the seventh cranial nerve caused lagophthalmos and decreased
lacrimal secretion; damage to the fifth cranial nerve caused corneal
hypesthesia. The nerves were damaged by the growth of vestibular tumors
in 1 patient, but in most patients they were damaged during
neurosurgical procedures.

Ragge et al. (1995) concluded that the most common ocular abnormalities
in NF2 are posterior subcapsular or capsular, cortical, or mixed lens
opacities, found in 33 of 49 patients (67%), and retinal hamartomas
found in 11 of 49 patients (22%). The types of cataract that were most
suggestive of NF2 were plaque-like posterior subcapsular or capsular
cataract and cortical cataract with onset under the age of 30 years.

Baser et al. (2003) confirmed the high prevalence of cataracts in young
NF2 patients. They suggested that the frequent occurrence of cataracts
before the tumor manifestations of NF2 indicated the usefulness of this
non-eighth nerve feature in the diagnosis of NF2 in children and
adolescents.

McLaughlin et al. (2007) identified 3 types of NF2-associated ocular
manifestations: juvenile posterior subcapsular cataract, epiretinal
membrane, and intrascleral schwannoma. Their histopathologic analysis
revealed that dysplastic lens cells accumulated just anterior to the
posterior lens capsule in juvenile posterior subcapsular cataract, and
that dysplastic Muller cells might be a major component of
NF2-associated epiretinal membrane. McLaughlin et al. (2007) concluded
that their findings suggested that a subset of glial cells with
epithelial features (Schwann cells, ependymal cells, and Muller cells)
might be particularly sensitive to loss of the NF2 gene.

DIAGNOSIS

In a review of NF2, Martuza and Eldridge (1988) defined criteria for the
diagnosis of both NF1 and NF2. An NIH Consensus Development Conference
(1988) concluded that the criteria for NF2 are met if a person is found
to have '(1) bilateral eighth nerve masses seen with appropriate imaging
techniques (e.g., CT or MRI); or (2) a first-degree relative with NF2
and either unilateral eighth nerve mass, or two of the following:
neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior
subcapsular lenticular opacity.' Pastores et al. (1991) demonstrated
that small (less than 8 mm) acoustic neuromas can be detected in
asymptomatic individuals by the use of gadolinium-enhanced MRI. They
demonstrated such neuromas in 2 asymptomatic children, aged 7 and 11
years, one of whom had normal audiometric and brainstem-evoked response
testing.

Using polymorphic DNA markers in a study of 13 NF2 kindreds, Ruttledge
et al. (1993) concluded that it is possible to determine, with a high
degree of certainty, the carrier status of about 85% of persons at risk.
Risk prediction was possible in every case in which DNA was available
from both parents. In 76% of informative individuals, it was possible to
assign a decreased risk of being carriers. Thus, the use of probes for
construction of chromosome 22 haplotypes for risk assessment should
result in a greatly reduced number of individuals who will require
periodic screening.

Gutmann et al. (1997) provided guidelines for the diagnostic evaluation
and multidisciplinary management of both NF1 and NF2. The criteria for
definite NF2 were bilateral vestibular schwannomas; or family history of
NF2 in 1 or more first-degree relative(s) plus (a) unilateral vestibular
schwannomas at age less than 30 years, or (b) any two of the following:
meningioma, glioma, schwannoma, or juvenile posterior subcapsular
lenticular opacities/juvenile cortical cataract. The criteria for
presumptive or probable NF2 was unilateral vestibular schwannomas at age
less than 30 years, plus at least one of the following: meningioma,
glioma, schwannoma, or juvenile posterior subcapsular lenticular
opacities/juvenile cortical cataract; or multiple meningiomas (two or
more) plus (a) unilateral vestibular schwannomas at age less than 30
years, or (b) one of the following: glioma, schwannoma, or juvenile
posterior subcapsular lenticular opacities/juvenile cortical cataract.

Kluwe et al. (2000) studied 40 skin tumors (36 schwannomas and 4
neurofibromas) from 20 NF2 patients, 15 of whom had NF2 mutations
previously identified in blood leukocytes. The detection rate of
constitutional mutations was higher in patients with skin tumors (65%)
than in patients without skin tumors (40%). Alterations in both NF2
alleles were found in 17 (43%) of the tumors. They concluded that loss
of a functional NF2 gene product is a critical event in the generation
of skin schwannomas and that mutation detection in skin tumors may be a
useful diagnostic tool in patients with skin tumors where the clinical
diagnosis of NF2 is ambiguous, or in unclear cases in which NF1 must be
excluded.

Baser et al. (2002) evaluated 4 previous sets of clinical diagnostic
criteria for NF2 developed by groups of experts: the NIH Consensus
Development Conference (1988), the Consensus Development Panel (1994) of
the NIH, the Manchester Group criteria reported by Evans et al. (1992),
and the National Neurofibromatosis Foundation (NNFF) criteria reported
by Gutmann et al. (1997). Baser et al. (2002) concluded that none of the
existing sets of criteria was adequate at initial assessment for
diagnosing people who present without bilateral vestibular schwannomas,
particularly people with a negative family history of NF2.

Baser et al. (2011) empirically developed and tested an improved set of
diagnostic criteria that used understanding of the natural history and
genetic characteristics of NF2 to increase sensitivity while maintaining
very high specificity. They used data from the UK Neurofibromatosis 2
Registry and Kaplan-Meier curves to estimate frequencies of clinical
features at various ages among patients with or without unequivocal NF2.
On the basis of this analysis, Baser et al. (2011) developed the Baser
criteria, a diagnostic system that incorporates genetic testing and
gives more weight to the most characteristic features and to those that
occur before 30 years of age. In an independent validation subset of
patients with unequivocal NF2, the Baser criteria increased diagnostic
sensitivity to 79% (9-15% greater than previous sets of criteria) while
maintaining 100% specificity at the age of onset of the first
characteristic sign of NF2.

- Mosaicism in NF2

Evans et al. (2007) showed that the chances of a de novo patient with
NF2 being mosaic for the underlying mutation in the NF2 gene increased
with age at presentation with vestibular schwannoma and was particularly
high in patients with unilateral presentation of vestibular schwannoma,
but who still had at least 2 further NF2-related tumors in order to
fulfill the Manchester criteria.

Evans and Wallace (2009) analyzed the mosaic risk in de novo patients
with NF2 by age at the time of vestibular schwannoma diagnosis. They
analyzed this risk in 4 age cohorts to derive figures for mosaicism and
offspring risk both before and after lymphocyte DNA testing with
sequencing and multiple ligation-dependent probe amplification. The
study was based on actual genetic testing of lymphocyte DNA in 402 de
novo patients and subsequent tumor testing in 51 patients with negative
blood analysis. The risk of NF2 to an offspring of a patient presenting
with bilateral vestibular schwannoma at less than 20 years of age was
29.3%, whereas the offspring risk for a patient presenting with
asymmetric disease after 40 years of age was only 5.5%, as there is a
99% chance that they are mosaic.

CLINICAL MANAGEMENT

Stereotactic radiosurgery is the principal alternative to microsurgical
resection for acoustic neuromas. The goals of radiosurgery are the
long-term prevention of tumor growth, maintenance of neurologic
function, and prevention of new neurologic deficits. Kondziolka et al.
(1998) evaluated 162 consecutive patients who underwent radiosurgery for
acoustic neuromas between 1987 and 1992, surveying the results between 5
and 10 years after the procedure. Resection had been performed
previously in 42 patients; in 13 patients, the tumor represented a
recurrence of disease after a previous total resection. The rate of
tumor control (with no resection required) was 98%. Radiosurgery was
believed to have been successful by all 30 patients who had undergone
surgery previously and by 81 (95%) of the 85 who had not. Pitts and
Jackler (1998) pointed out that when radiotherapy is considered for a
benign, surgically curable tumor in a young patient, the risk of
inducing a secondary tumor must be seriously weighed. The risk of
intracranial arterial occlusion from external-beam irradiation must also
be considered, although there had been no reports of accelerated
atherosclerosis after radiosurgery. The anterior inferior cerebellar
artery, which is the primary source of blood supply to the lateral pons
and upper medulla, lies right next to the surface of acoustic neuromas.

MAPPING

Seizinger et al. (1986) found loss of genes on chromosome 22 in acoustic
neuromas; i.e., whereas normal tissue was heterozygous, tumor tissue was
hemizygous (or homozygous) for the polymorphic markers SIS (190040),
IGLC (147220), and the anonymous DNA locus D22S1. They were prompted to
undertake the study by analogy to retinoblastoma and Wilms tumor and by
the facts that meningioma occurs in association with familial acoustic
neuroma and that cytologic change in chromosome 22 is frequent in
meningioma (see 607174). Seizinger et al. (1987) found specific loss of
alleles from chromosome 22 in 2 acoustic neuromas, 2 neurofibromas, and
1 meningioma from patients with bilateral acoustic neurofibromatosis. In
each case, a partial deletion occurred with a breakpoint distal to the
D22S9 locus in band 22q11. Wertelecki et al. (1988) confirmed
localization of the causative gene on chromosome 22 (22q11.21-q13.1) by
demonstration of linkage in family studies to markers on chromosome 22.
Wertelecki et al. (1988) also presented the clinical data on 15 affected
male and 8 affected female members of the 1 large kindred they studied
for linkage data.

Rouleau et al. (1990) identified markers on chromosome 22 bracketing the
NF2 gene which are therefore useful for accurate presymptomatic and
prenatal diagnosis, as well as for isolating the defective gene. Through
linkage analysis on 12 families with NF2, Narod et al. (1992) confirmed
the assignment of the NF2 gene to chromosome 22 and concluded that there
is no evidence of genetic heterogeneity in NF2. They indicated that the
presence of bilateral vestibular schwannomas, as they termed the
acoustic neuromas, is sufficient for the diagnosis.

Using 8 polymorphic loci on chromosome 22 to study tumor and
constitutional DNAs isolated from 39 unrelated patients with sporadic or
NF2-associated acoustic neuromas, meningiomas, schwannomas, and
ependymomas, Wolff et al. (1992) found 2 tumors with loss of
heterozygosity (LOH) patterns consistent with the presence of chromosome
22 terminal deletions. By use of additional polymorphic markers, the
terminal deletion breakpoint in one of the tumors, an acoustic neuroma
from an NF2 patient, was mapped within the previously defined NF2
region. In addition, they identified a sporadic acoustic neuroma with an
LOH pattern consistent with mitotic recombination or deletion and
reduplication. The findings lent further support to the recessive tumor
suppressor model for the NF2 gene. Arai et al. (1992) described a
patient with bilateral acoustic neurinomas and other tumors in the
central nervous system and a constitutional translocation
t(4;22)(q12;q12.2). Thus, 22q12.2 is a refined localization for the NF2
gene. The same karyotype that was seen in cultured peripheral
lymphocytes was found in a paraspinal neurinoma. The patient's father
was also a carrier of the translocation but he had no clinical symptoms
of NF2, nor did other relatives. As explanation for the failure of
expression in the father, Arai et al. (1992) suggested various
possibilities including nonpenetrance, mosaicism, or genetic imprinting.
They quoted Kanter et al. (1980) as demonstrating earlier onset of
symptoms when NF2 is transmitted by the mother. Bovie et al. (2003) also
reported a case of neurofibromatosis 2 in a patient with a balanced X;22
translocation. The patient presented with a large abdominal schwannoma
and intellectual disability. A clinical diagnosis of NF2 was made when
bilateral vestibular schwannomas were found on MRI. With demonstration
of a de novo balanced reciprocal translocation between chromosome X and
22, the disorder in this patient was initially assumed to have been
caused by the loss of NF2 at the translocation breakpoint. This was
found, however, not to be the case; the breakpoint was 6 Mb centromeric
to the NF2 gene and no mutations or deletions were found in the germline
NF2 gene of the patient. The X-inactivation pattern in lymphocytes was
100% skewed to inactivate the normal X chromosome as predicted for
X;autosome translocations whereas in tumor tissue there was aberrant X
inactivation of the opposite derivative X chromosome. The mechanism of
the disease in this case was thought to be that a proportion of Schwann
cells had 1 NF2 allele acting as a functional null by virtue of NF2
being translocated to the X chromosome and aberrant X inactivation of
the X;autosome.

MOLECULAR GENETICS

Rouleau et al. (1993) provided incontrovertible evidence that the NF2
gene (607379) is the site of the mutations causing neurofibromatosis II
by demonstrating germline and somatic SCH mutations in NF2 patients and
in NF2-related tumors. For description of the mutations identified in
the NF2 gene and for a discussion of somatic mosaicism, see 607379.

Wu et al. (1998) identified 15 patients from a series of 537 with
unilateral vestibular schwannomas who also had 1 or more of the
following: other tumors (10 of 15), features of NF2 (3 of 15), or a
family history of neurogenic tumors (5 of 15). No germline NF2 mutations
were detected, and in 7 of 9 cases where tumor material was available
for analysis, a germline mutation in NF2 was excluded. Wu et al. (1998)
concluded that most instances of unilateral vestibular schwannoma which
do not fulfill criteria for NF2 represent chance occurrences.

Baser et al. (2002) reported a patient with NF2 who developed malignant
mesothelioma after a long occupational exposure to asbestos. Genetic
analysis of the tumor tissue showed loss not only of chromosome 22 but
also of chromosomes 14 and 15, and gain of chromosome 7. Baser et al.
(2002) suggested that an individual with a constitutional mutation of an
NF2 allele, as in NF2, is more susceptible to mesothelioma. Although
mesothelioma is not a common feature in NF2, the authors cited the
observation of Knudson (1995) that somatic mutations of a tumor
suppressor gene, such as NF2, RB1 (614041), or p53 (191170), can be
common in a tumor type that is not characteristic of the hereditary
disorder, perhaps due to the proliferative timing of the cells involved.

In a family with the mild or so-called Gardner type of neurofibromatosis
type II, Watson et al. (1993) defined a submicroscopic deletion on
chromosome 22q which involved the neurofilament heavy chain locus (NEFH;
162230) but did not extend as far as the Ewing sarcoma region (EWSR1;
133450) proximally or the leukemia inhibitory factor locus (LIF; 159540)
distally. They estimated that the deletion was about 700 kb long.

Mohyuddin et al. (2002) identified 45 patients aged 30 years or less at
the onset of symptoms of unilateral vestibular schwannoma. Molecular
genetic analysis of the NF2 gene was performed in all 45 patients and on
28 tumor samples. No pathogenic NF2 mutations were identified in any of
the blood samples. NF2 point mutations were identified in 21 of 28 (75%)
tumor samples and LOH in 21 of 28 (75%) tumor samples. Overlap, i.e.,
both mutational hits, were identified in 18 of 28 (65%) tumor samples.
They observed 1 multilobular tumor in which 1 (presumably first hit)
mutation was confirmed which was common to different foci of the tumor,
while the second mutational event differed between foci. The molecular
findings in this patient were consistent with somatic mosaicism for NF2
and a clinical diagnosis was confirmed with the presence of 2
meningiomas on a follow-up MRI scan.

Tsilchorozidou et al. (2004) reported 5 NF2 patients with constitutional
rearrangements of chromosome 22 and vestibular schwannomas, multiple
intracranial meningiomas, and spinal tumors. The authors noted that an
additional 10 NF2 patients with constitutional NF2 deletions had been
discovered using NF2 FISH in their laboratory, and suggested that
chromosome analysis with FISH might be a useful first screen prior to
molecular testing in NF2 patients.

GENOTYPE/PHENOTYPE CORRELATIONS

Parry et al. (1996) identified mutations in the NF2 gene in 66% of 32
patients; 20 different mutations were found in 21 patients. They
suggested that their results confirmed the association between nonsense
and frameshift mutations and clinical manifestations compatible with
severe disease. They stated that their data raised questions regarding
the role of other factors, in addition to the intrinsic properties of
individual mutations, that might influence the phenotype. Ruttledge et
al. (1996) reported that when individuals harboring protein-truncating
mutations are compared with patients having single codon alterations, a
significant correlation (p less than 0.001) with clinical outcome is
observed. They noted that 24 of 28 patients with mutations that cause
premature truncation of the NF2 protein presented with severe
phenotypes. In contrast, all 16 cases from 3 families with mutations
that affect only a single amino acid had mild NF2.

Evans et al. (1998) reported 42 cases of NF2 from 38 families with
truncating mutations. The average age of onset of symptoms was 19 years
and age at diagnosis 22.4 years. Fifty-one cases from 16 families (15
with splice site mutations, 18 with missense mutations, and 18 with
large deletions) had an average age of onset of 27.8 years and age at
diagnosis of 33.4 years. Subjects with truncating mutations were
significantly more likely to develop symptoms before 20 years of age (p
less than 0.001) and to develop at least 2 symptomatic CNS tumors in
addition to vestibular schwannoma before 30 years (p less than 0.001).
There were significantly fewer multigenerational families with
truncating mutations.

Kehrer-Sawatzki et al. (1997) reported a patient with NF2 and a ring
chromosome 22 (46,XX,r(22)/45,XX,-22). Severe manifestations included
multiple meningiomas, spinal and peripheral neurinomas, and bilateral
vestibular schwannomas. The patient was also severely mentally retarded,
a feature not usually associated with NF2. The authors hypothesized that
a mutation in the NF2 gene of the normal chromosome 22, in addition to
the loss of the ring 22 in many cells during mitosis, could explain the
presence of multiple tumors. Using a meningioma cell line lacking the
ring chromosome, Kehrer-Sawatzki et al. (1997) searched for deletions,
rearrangements, or other mutations of the NF2 gene on the normal
chromosome 22; no such alterations were found. The authors concluded
that the loss of the entire chromosome 22 and its multiple tumor
suppressor genes may have led to the severe phenotype in this patient.

In 406 patients from the population-based United Kingdom NF2 registry,
Baser et al. (2004) evaluated genotype/phenotype correlations for
various types of non-VIII nerve tumors using regression models with the
additional covariates of current age and type of treatment center
(specialty or nonspecialty). The models also permitted consideration of
intrafamilial correlation. The authors found statistically significant
genotype/phenotype correlations for intracranial meningiomas, spinal
tumors, and peripheral nerve tumors. People with constitutional NF2
missense mutations, splice site mutations, large deletions, or somatic
mosaicism had significantly fewer tumors than did people with
constitutional nonsense or frameshift NF2 mutations. In addition, there
were significant intrafamilial correlations for intracranial meningiomas
and spinal tumors, after adjustment for the type of constitutional NF2
mutation. Baser et al. (2004) concluded that the type of constitution
NF2 mutation is an important determinant of the number of NF2-associated
intracranial meningiomas, spinal tumors, and peripheral nerve tumors.

In 831 patients from 528 NF2 families, Baser et al. (2005) analyzed
location of splice site mutations and severity of NF2, using age at
onset of symptoms and number of intracranial meningiomas as indicators.
They found that individuals with splice site mutations in exons 1 to 5
had more severe disease than those with splice site mutations in exons
11 to 15. Baser et al. (2005) confirmed the previously reported
observation that missense mutations are usually associated with mild
NF2.

HISTORY

Baser et al. (2004) noted that initial genotype/phenotype correlation
studies of NF2 were limited by the generality of the definition of
disease severity, which was often reported only as 'mild,' 'moderate,'
or 'severe.' The mild and severe disease categories corresponded to the
historical nomenclature of 'Gardner' (mild) and 'Wishart' (severe)
subtypes, which were based on the clinical observation that the severity
of NF2 tended to 'run true' within a family (Wishart, 1822; Gardner and
Frazier, 1930). Another category, 'Lee-Abbott' (Lee and Abbott, 1969),
which corresponds to very severe NF2, was not consistently adopted by
subsequent studies.

CYTOGENETICS

Krone and Hogemann (1986) found monosomy 22 as a predominant numerical
anomaly in cultured cells grown from peripheral neurofibromas in
patients described simply as suffering 'from sporadic peripheral NF.'
Duncan et al. (1987) observed a ring chromosome 22 in a man with an
atypical form of neurofibromatosis. He lacked a family history of NF,
cafe-au-lait spots, and axillary freckling. He had multiple
neurofibromas and a plexiform neuroma. By in situ hybridization, Duncan
et al. (1987) showed that both the normal chromosome 22 and the ring
chromosome 22 carried this gene.

*FIELD* SA
Martuza and Ojemann (1982); Nager (1964); Niimura (1973); Perez
Demoura et al. (1969); Rouleau et al. (1987); Rouleau et al. (1987);
Siggers et al. (1975)
*FIELD* RF
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Kida, M.; Ichimura, K.; Yuasa, Y.; Tonomura, A.: Constitutional translocation
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2. Asthagiri, A. R.; Parry, D. M.; Butman, J. A.; Kim, H. J.; Tsilou,
E. T.; Zhuang, Z.; Lonser, R. R.: Neurofibromatosis type 2. Lancet 373:
1974-1986, 2009.

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n. M.; Gutmann, D. H.; Pitts, L. H.; Jackler, R. K.; Testa, J. R.
: Neurofibromatosis 2 and malignant mesothelioma. Neurology 59:
290-291, 2002.

4. Baser, M. E.; Friedman, J. M.; Aeschliman, D.; Joe, H.; Wallace,
A. J.; Ramsden, R. T.; Evans, D. G. R.: Predictors of the risk of
mortality in neurofibromatosis 2. Am. J. Hum. Genet. 71: 715-723,
2002.

5. Baser, M. E.; Friedman, J. M.; Evans, D. G. R.: Maternal gene
effect in neurofibromatosis 2: fact or artifact? (Letter) J. Med.
Genet. 38: 783-784, 2001.

6. Baser, M. E.; Friedman, J. M.; Joe, H.; Shenton, A.; Wallace, A.
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7. Baser, M. E.; Friedman, J. M.; Wallace, A. J.; Ramsden, R. T.;
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8. Baser, M. E.; Kuramoto, L.; Joe, H.; Friedman, J. M.; Wallace,
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9. Baser, M. E.; Kuramoto, L.; Joe, H.; Friedman, J. M.; Wallace,
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10. Baser, M. E.; Kuramoto, L.; Woods, R.; Joe, H.; Friedman, J. M.;
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*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Ears];
Hearing loss;
Tinnitus;
[Eyes];
Juvenile posterior subcapsular lenticular opacities;
Juvenile cortical cataract;
Epiretinal membranes;
Retinal hamartoma;
No Lisch nodules

SKIN, NAILS, HAIR:
[Skin];
Occasional cafe-au-lait spots;
Occasional neurofibroma;
Schwannoma

NEUROLOGIC:
[Central nervous system];
Headache;
Ataxia;
[Peripheral nervous system];
Peripheral neuropathy

NEOPLASIA:
Meningioma;
Glioma;
Vestibular Schwannoma (over 90% of patients);
Ependymoma;
Neurofibroma;
Astrocytoma

MISCELLANEOUS:
Incidence of 1 in 25,000 livebirths;
Nearly 100% penetrance by 60 years of age;
Approximately half of the mutations are de novo

MOLECULAR BASIS:
Caused by mutations in merlin (NF2, 101000.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 11/3/2009
Ada Hamosh - reviewed: 4/14/2000
Kelly A. Przylepa - revised: 2/18/2000

*FIELD* ED
joanna: 07/23/2013
joanna: 4/26/2013
ckniffin: 11/3/2009
ckniffin: 10/18/2005
joanna: 4/14/2000
kayiaros: 2/25/2000
kayiaros: 2/18/2000

*FIELD* CN
Ada Hamosh - updated: 10/1/2012
Nara Sobreira - updated: 3/10/2010
Cassandra L. Kniffin - updated: 11/3/2009
Jane Kelly - updated: 8/13/2007
Marla J. F. O'Neill - updated: 9/19/2005
Marla J. F. O'Neill - updated: 8/27/2004
Victor A. McKusick - updated: 8/12/2004
Victor A. McKusick - updated: 1/13/2004
Victor A. McKusick - updated: 12/29/2003
Cassandra L. Kniffin - updated: 2/13/2003
Cassandra L. Kniffin - reorganized: 1/28/2003
Patricia A. Hartz - updated: 11/22/2002
Cassandra L. Kniffin - updated: 10/29/2002
Victor A. McKusick - updated: 10/28/2002
Michael J. Wright - updated: 10/22/2002
Cassandra L. Kniffin - updated: 10/3/2002
George E. Tiller - updated: 9/6/2002
Cassandra L. Kniffin - updated: 6/7/2002
George E. Tiller - updated: 12/12/2001
George E. Tiller - updated: 7/23/2001
George E. Tiller - updated: 6/19/2001
Victor A. McKusick - updated: 5/11/2001
George E. Tiller - updated: 4/19/2001
Victor A. McKusick - updated: 11/28/2000
Victor A. McKusick - updated: 9/25/2000
George E. Tiller - updated: 9/13/2000
Gary A. Bellus - updated: 6/9/2000
Paul Brennan - updated: 4/11/2000
Paul J. Converse - updated: 4/4/2000
Victor A. McKusick - updated: 5/14/1999
Ada Hamosh - updated: 4/8/1999
Michael J. Wright - updated: 2/12/1999
Victor A. McKusick - updated: 1/6/1999
Victor A. McKusick - updated: 11/30/1998
Victor A. McKusick - updated: 9/16/1998
Michael J. Wright - updated: 6/30/1998
Victor A. McKusick - updated: 2/16/1998
Ethylin Wang Jabs - updated: 7/9/1997
Orest Hurko - updated: 11/6/1996
Moyra Smith - updated: 10/1/1996
Moyra Smith - updated: 9/13/1996
Stylianos E. Antonarakis - updated: 7/4/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 11/02/2012
alopez: 10/3/2012
terry: 10/1/2012
carol: 6/17/2011
carol: 3/31/2010
carol: 3/24/2010
terry: 3/10/2010
carol: 11/23/2009
wwang: 11/19/2009
terry: 11/6/2009
ckniffin: 11/3/2009
terry: 6/3/2009
terry: 1/7/2009
carol: 8/5/2008
carol: 8/13/2007
wwang: 10/4/2005
terry: 9/19/2005
terry: 2/22/2005
carol: 8/27/2004
terry: 8/27/2004
tkritzer: 8/20/2004
tkritzer: 8/16/2004
terry: 8/12/2004
carol: 2/6/2004
tkritzer: 1/30/2004
terry: 1/13/2004
cwells: 12/30/2003
terry: 12/29/2003
carol: 2/24/2003
ckniffin: 2/13/2003
carol: 1/28/2003
ckniffin: 1/13/2003
mgross: 11/22/2002
carol: 11/13/2002
ckniffin: 10/29/2002
carol: 10/29/2002
tkritzer: 10/28/2002
carol: 10/28/2002
tkritzer: 10/23/2002
terry: 10/22/2002
carol: 10/21/2002
ckniffin: 10/3/2002
cwells: 9/6/2002
alopez: 8/1/2002
alopez: 7/18/2002
alopez: 7/16/2002
carol: 6/17/2002
ckniffin: 6/7/2002
cwells: 12/18/2001
cwells: 12/12/2001
cwells: 7/27/2001
cwells: 7/23/2001
cwells: 6/20/2001
cwells: 6/19/2001
carol: 6/8/2001
mcapotos: 5/22/2001
mcapotos: 5/17/2001
terry: 5/11/2001
alopez: 5/11/2001
cwells: 5/1/2001
cwells: 4/19/2001
mcapotos: 12/5/2000
mcapotos: 12/4/2000
terry: 11/28/2000
mcapotos: 10/3/2000
mcapotos: 9/29/2000
terry: 9/25/2000
alopez: 9/13/2000
alopez: 6/9/2000
alopez: 4/11/2000
carol: 4/4/2000
mgross: 6/3/1999
mgross: 5/26/1999
terry: 5/14/1999
alopez: 4/8/1999
mgross: 2/16/1999
terry: 2/12/1999
carol: 1/18/1999
terry: 1/6/1999
carol: 12/2/1998
terry: 11/30/1998
carol: 11/10/1998
alopez: 9/18/1998
terry: 9/16/1998
alopez: 7/6/1998
terry: 6/30/1998
terry: 6/3/1998
terry: 5/29/1998
alopez: 5/14/1998
mark: 2/25/1998
terry: 2/16/1998
alopez: 9/8/1997
alopez: 9/4/1997
alopez: 7/9/1997
alopez: 6/3/1997
terry: 3/31/1997
mark: 11/6/1996
terry: 10/23/1996
mark: 10/1/1996
mark: 9/13/1996
carol: 7/4/1996
terry: 7/1/1996
mark: 6/7/1996
joanna: 5/6/1996
mark: 3/3/1996
terry: 2/26/1996
mark: 2/16/1996
mark: 2/13/1996
mark: 12/12/1995
terry: 12/11/1995
mark: 9/10/1995
terry: 5/25/1995
carol: 2/17/1995
jason: 7/25/1994
mimadm: 6/26/1994
warfield: 4/7/1994

MIM 156240
*RECORD*
*FIELD* NO
156240
*FIELD* TI
#156240 MESOTHELIOMA, MALIGNANT; MESOM
*FIELD* TX
A number sign (#) is used with this entry because somatic mutations in
read moreseveral genes have been identified in malignant mesothelioma. These
genes include WT1 (607102) on chromosome 11p13, BCL10 (603517) on
chromosome 1p22, CDKN2A (600160) on chromosome 9p21, NF2 (607379) on
chromosome 22q12, and BAP1 (603089) on chromosome 3p21.

DESCRIPTION

Malignant mesothelioma is an aggressive neoplasm of the serosal lining
of the chest etiologically linked to asbestos. It is diagnosed in
approximately 2,000 to 3,000 individuals annually in the United States,
most of whom die within 2 years of diagnosis (summary by Bott et al.,
2011).

See also 614327 for a tumor predisposition syndrome that may contribute
to the development of malignant mesothelioma upon asbestos exposure and
is caused by germline mutation in the BAP1 gene (603089) on chromosome
3p21.

INHERITANCE

In connection with the etiology of mesothelioma, primary attention has
appropriately been focused on environmental factors, particularly
asbestos exposure. Li et al. (1978) reported pleural mesothelioma in the
wife and daughter of a man who worked for about 25 years as a pipe
insulator at a shipyard and who also developed pulmonary asbestosis and
lung cancer. The wife and daughter had no asbestos exposure other than
that from the man's clothing.

Risberg et al. (1980) described a family in Sweden in which the father,
3 brothers and a sister died of malignant mesothelioma. Four of the 5
probably had had asbestos exposure in the building industry. All were
smokers. The area showed low incidence of malignant mesothelioma. There
were 8 other sibs who were unaffected at the time of report (2 had died
of other causes). The authors suggested that, in addition to smoking and
asbestos, genetic factors may be involved in the pathogenesis.

Martensson et al. (1984) observed malignant mesothelioma in 2 pairs of
sibs and raised a question of a hereditary predisposing factor.

Although common household or occupational exposure may be responsible
for familial aggregation, Lynch et al. (1985) also raised the question
of a host factor in the occurrence and/or the histologic characteristics
of mesothelioma. They reported brothers who died of malignant pleural
mesothelioma.

Hammar et al. (1989) reported 3 brothers who worked in the asbestos
insulation business and developed mesothelioma. In a second family, a
father, who was occupationally exposed to asbestos, died from a
tubulopapillary peritoneal mesothelioma 11 years before his son died
from a peritoneal mesothelioma of identical histologic type. Although it
is possible that the son was secondarily exposed to asbestos from the
father's work clothes, quantitative asbestos analysis of the son's lung
tissue showed numbers of asbestos bodies well within the lower limits
seen in the general urban population with no occupational exposure to
asbestos. The simulation of mendelian dominant inheritance was indicated
by the occurrence of familial mesothelioma contracted as an infant by a
woman who died of this disorder at age 32.

A combination of asbestos exposure and host predisposition was suggested
also by the report of pleural malignant mesothelioma in 3 sisters and a
male cousin by Ascoli et al. (1998). The 3 women had worked in the same
confectionary shop as pastry cooks and/or pastry shop assistants; the
use of an asbestos-insulated oven was the putative source of exposure.
The man had occupational exposure as a heating system insulation worker.
Malignant cancers were reported in other relatives (larynx in a brother;
pleura and lung in a mother; lung in an aunt and uncle; and lung in a
cousin).

Erionite present in stones used to build the villages of Karain and
Tuzkoy, Turkey, mined from nearby caves, is purported to cause
mesothelioma in half of the villagers. Roushdy-Hammady et al. (2001)
constructed genetic epidemiology maps to test whether some villagers
were genetically predisposed to mesothelioma. Analysis of a 6-generation
extended pedigree of 526 individuals showed that mesothelioma was
genetically transmitted, probably in an autosomal dominant way. The
incidence of malignant mesothelioma in immigrants from Karain and Tuzkoy
living in Sweden and Germany was similar to or higher than that of the 2
Turkish villages, suggesting that erionite is only a cofactor in the
cause of malignant mesothelioma in genetically predisposed individuals.
This suggestion is supported by data showing an absence of mesothelioma
cases in the towns of Karlik and other nearby villages, whose houses
contain a similar amount of erionite.

Carbone and Testa (2001) claimed that genetic susceptibility to
mesothelioma in the Cappadocian region of Turkey was conclusively
demonstrated by the study of Roushdy-Hammady et al. (2001). Saracci and
Simonato (2001) presented several reasons why the study did not prove
genetic causation. One of the reasons was that before 1978, when endemic
mesothelioma was recognized in this area by the study of Baris et al.
(1978), mesothelioma was diagnosed as tuberculosis, lung cancer,
metastatic cancers, or other disorders. Some members of the family in
the reported pedigree must have died no later than 1960, long before
local recognition of the disease. Dogan et al. (2001) defended the
conclusion concerning a genetic factor for susceptibility to erionite
carcinogenicity. Saracci and Simonato (2001) pointed out that the
question has wide public health implications, given the weight that a
genetic factor may carry when debating liability in asbestos-related
mesotheliomas.

CYTOGENETICS

In 24 human malignant mesothelioma cell lines derived from untreated
primary tumors, Balsara et al. (1999) performed comparative genomic
hybridization analysis to identify chromosomal imbalances. Chromosomal
losses accounted for the majority of genomic imbalances. The most
frequent underrepresented segments were 22q (58%) and 15q11.1-q21 (54%).
To map more precisely the region of 15q deletion, loss of heterozygosity
analyses were performed with a panel of polymorphic microsatellite
markers distributed along 15q, which defined a minimal region of
chromosomal loss at 15q11.1-q15. Balsara et al. (1999) suggested that
this region harbors a putative tumor suppressor gene whose loss or
inactivation may contribute to the pathogenesis of many malignant
mesotheliomas.

Musti et al. (2002) described a family in which 3 sisters were affected
by malignant mesothelioma, 2 pleural and 1 peritoneal, and 1 brother was
affected by pleural plaques. All family members had been subjected to
previous asbestos exposure of environmental-residential type. For 13
years, from 1951 to 1964, their housing was provided by the father's
employer, an asbestos cement factory; the factory warehouse was on the
ground floor of the building in which they lived. DNA extracted from
paraffin-embedded malignant mesothelioma samples was used to search for
chromosomal alterations by comparative genomic hydridization (CGH). A
loss at chromosome 9p, a frequent event in malignant mesothelioma, was
the only change in 2 of the sisters, which suggested that this region
may be the site of 1 or more oncosuppressor genes that play an important
role in the development of the disease and in inducing greater genetic
susceptibility to the carcinogenic effects of asbestos.

MOLECULAR GENETICS

By immunohistochemical analysis of archival paraffin specimens and tumor
cell lines, Kratzke et al. (1995) found that p16(INK4) (CDKN2; 600160)
was expressed in a nonsmall cell lung cancer cell line but not in 12 of
12 primary thoracic mesotheliomas and 15 of 15 mesothelioma cell lines.
All tumor specimens and the tumor cell lines showed expression of
wildtype RB1 protein (614041). In addition, transfection of CDKN2
suppressed the growth of 2 independent mesothelioma cell lines. The
authors concluded that inactivation of the CDKN2 gene is an essential
step in the etiology of malignant mesotheliomas.

Baser et al. (2002) reported a patient with neurofibromatosis type II
(NF2; 101000) who developed malignant mesothelioma after a long
occupational exposure to asbestos. Genetic analysis of the tumor tissue
showed loss not only of chromosome 22, where the NF2 gene (607379) is
located, but also of chromosomes 14 and 15, and gain of chromosome 7.
Baser et al. (2002) suggested that an individual with a constitutional
mutation of an NF2 allele is more susceptible to mesothelioma. Although
mesothelioma is not a common feature in NF2, the authors cited the
observation of Knudson (1995) that somatic mutations of a tumor
suppressor gene, such as NF2, RB1, or p53 (191170), can be common in a
tumor type that is not characteristic of the hereditary disorder,
perhaps due to the proliferative timing of the cells involved.

By studying copy number alterations followed by candidate gene
sequencing of 53 primary malignant pleural mesothelioma (MPM) samples,
Bott et al. (2011) identified the BAP1 gene (603089) on chromosome
3p21.1 as a commonly somatically inactivated gene. Twelve (23%) of 53
tumors had nonsynonymous mutations, and 16 (30%) had at least single
copy genomic loss of the BAP1 locus. Tumors with mutations showed loss
of nuclear staining for BAP1. BAP1 losses were confirmed in an
independent collection of MPM tumors. The somatic nature of the
mutations was confirmed in all tumors that had matched normal tissue
available. Knockdown of BAP1 in mesothelioma cell lines expressing
wildtype BAP1 resulted in proliferation defects with an accumulation of
cells in S phase and also downregulated E2F (see, e.g.,
189971)-responsive genes. Given the known role of BAP1 in regulatory
ubiquitination of histones, the findings suggested transcriptional
deregulation as a pathogenic mechanism. Sequencing also confirmed
frequent inactivating mutations in the NF2 gene (11 of 53; 21%) and
identified previously undescribed missense mutations in the LATS2 gene
(604861) (2 of 53; 3.8%) and the LATS1 gene (603473) (2 of 53; 3.8%).

*FIELD* SA
Anderson et al. (1976); Li et al. (1989)
*FIELD* RF
1. Anderson, H. A.; Lilis, R.; Daum, S. M.; Fischbein, A. S.; Selikoff,
I. J.: Household-contact asbestos neoplastic risk. Ann. N.Y. Acad.
Sci. 271: 311-323, 1976.

2. Ascoli, V.; Scalzo, C. C.; Bruno, C.; Facciolo, F.; Lopergolo,
M.; Granone, P.; Nardi, F.: Familial pleural malignant mesothelioma:
clustering in three sisters and one cousin. Cancer Lett. 130: 203-207,
1998.

3. Balsara, B. R.; Bell, D. W.; Sonoda, G.; De Rienzo, A.; du Manoir,
S.; Jhanwar, S. C.; Testa, J. R.: Comparative genomic hybridization
and loss of heterozygosity analyses identify a common region of deletion
at 15q11.1-15 in human malignant mesothelioma. Cancer Res. 59: 450-454,
1999.

4. Baris, Y. I.; Sahin, A. A.; Ozesmi, M.; Kerse, I.; Ozen, E.; Kolacan,
B.; Altinors, A.; Goktepeli, A.: An outbreak of pleural mesothelioma
and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia. Thorax 33:
181-192, 1978.

5. Baser, M. E.; De Rienzo, A.; Altomare, D.; Balsara, B. R.; Hedrick,
N. M.; Gutmann, D. H.; Pitts, L. H.; Jackler, R. K.; Testa, J. R.
: Neurofibromatosis 2 and malignant mesothelioma. Neurology 59:
290-291, 2002.

6. Bott, M.; Brevet, M.; Taylor, B. S.; Shimizu, S.; Ito, T.; Wang,
L.; Creaney, J.; Lake, R. A.; Zakowski, M. F.; Reva, B.; Sander, C.;
Delsite, R.; Powell, S.; Zhou, Q.; Shen, R.; Olshen, A.; Rusch, V.;
Ladanyi, M.: The nuclear deubiquitinase BAP1 is commonly inactivated
by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nature
Genet. 43: 668-672, 2011.

7. Carbone, M.; Testa, J. R.: Genetic susceptibility and familial
malignant mesothelioma. (Letter) Lancet 357: 1804 only, 2001.

8. Dogan, A. U.; Baris, Y. I.; Emri, S.; Testa, J. R.; Carbone, M.
: Familial malignant mesothelioma: authors' reply. (Letter) Lancet 358:
1813-1814, 2001.

9. Hammar, S. P.; Bockus, D.; Remington, F.; Freidman, S.; LaZerte,
G.: Familial mesothelioma: a report of two families. Hum. Path. 20:
107-112, 1989.

10. Knudson, A.: Asbestos and mesothelioma: genetic lessons from
a tragedy. Proc. Nat. Acad. Sci. 92: 10819-10820, 1995.

11. Kratzke, R. A.; Otterson, G. A.; Lincoln, C. E.; Ewing, S.; Oie,
H.; Geradts, J.; Kaye, F. J.: Immunohistochemical analysis of the
p16(INK4) cyclin-dependent kinase inhibitor in malignant mesothelioma. J.
Nat. Cancer Inst. 87: 1870-1875, 1995.

12. Li, F. P.; Dreyfus, M. G.; Antman, K. H.: Asbestos-contaminated
nappies and familial mesothelioma. (Letter) Lancet 333: 909-910,
1989. Note: Originally Volume I.

13. Li, F. P.; Lokich, J.; Lapey, J.; Neptune, W. B.; Wilkins, E.
W., Jr.: Familial mesothelioma after intense asbestos exposure at
home. JAMA 240: 467 only, 1978.

14. Lynch, H. T.; Katz, D.; Markvicka, S. E.: Familial mesothelioma:
review and family study. Cancer Genet. Cytogenet. 15: 25-35, 1985.

15. Martensson, G.; Larsson, S.; Zettergre, L.: Malignant mesothelioma
in two pairs of siblings: is there a hereditary predisposing factor? Europ.
J. Resp. Dis. 65: 179-184, 1984.

16. Musti, M.; Cavone, D.; Aalto, Y.; Scattone, A.; Serio, G.; Knuutila,
S.: A cluster of familial malignant mesothelioma with del(9p) as
the sole chromosomal anomaly. Cancer Genet. Cytogenet. 138: 73-76,
2002.

17. Risberg, B.; Nickels, J.; Wagermark, J.: Familial clustering
of malignant mesothelioma. Cancer 45: 2422-2427, 1980.

18. Roushdy-Hammady, I.; Siegel, J.; Emri, S.; Testa, J. R.; Carbone,
M.: Genetic-susceptibility factor and malignant mesothelioma in the
Cappadocian region of Turkey. Lancet 357: 444-445, 2001.

19. Saracci, R.; Simonato, L.: Familial malignant mesothelioma. (Letter) Lancet 358:
1813 only, 2001.

*FIELD* CS

Oncology:
Malignant mesothelioma

Inheritance:
Hereditary predisposing factor

*FIELD* CN
Cassandra L. Kniffin - updated: 8/8/2011
Patricia A. Hartz - updated: 1/15/2004
Victor A. McKusick - updated: 1/10/2003
Cassandra L. Kniffin - updated: 10/3/2002
Victor A. McKusick - updated: 2/14/2002
Ada Hamosh - updated: 4/26/2001
Victor A. McKusick - updated: 3/24/1999
Victor A. McKusick - updated: 2/19/1999

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
joanna: 12/20/2011
carol: 12/15/2011
carol: 11/9/2011
ckniffin: 11/8/2011
ckniffin: 11/3/2011
wwang: 8/12/2011
ckniffin: 8/8/2011
carol: 6/17/2011
terry: 6/3/2009
terry: 1/30/2009
joanna: 3/18/2004
mgross: 1/15/2004
carol: 1/28/2003
tkritzer: 1/15/2003
terry: 1/10/2003
carol: 10/21/2002
ckniffin: 10/3/2002
terry: 6/27/2002
carol: 2/20/2002
cwells: 2/15/2002
terry: 2/14/2002
mcapotos: 5/7/2001
terry: 4/26/2001
kayiaros: 7/8/1999
mgross: 4/2/1999
mgross: 3/30/1999
terry: 3/24/1999
carol: 2/22/1999
terry: 2/19/1999
mimadm: 11/6/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
root: 5/18/1989
carol: 4/3/1989

MIM 162091
*RECORD*
*FIELD* NO
162091
*FIELD* TI
#162091 SCHWANNOMATOSIS
;;NEURILEMMOMATOSIS, CONGENITAL CUTANEOUS
*FIELD* TX
A number sign (#) is used with this entry because mutation in the tumor
read moresuppressor gene SMARCB1 (601607) can cause germline-transmissible
schwannomatosis.

Individual schwannoma tumors from patients with schwannomatosis have
been found to harbor somatic mutations in SMARCB1 or the neurofibromin-2
gene (NF2; 607379).

DESCRIPTION

Schwannomatosis, also known as neurilemmomatosis, first reported by
Niimura (1973) as neurofibromatosis type 3, is characterized by multiple
cutaneous neurilemmomas and spinal schwannomas, without acoustic tumors
or other signs of neurofibromatosis I (NF1; 162200) or neurofibromatosis
II (NF2; 101000). In neurilemmomas, the tumor consists of Schwann cells.
Some patients may develop meningiomas (van den Munckhof et al., 2012).

CLINICAL FEATURES

Swensen et al. (2009) reported a family with hereditary schwannomatosis
spanning 4 generations associated with a germline duplication in the
SMARCB1 gene (601607.0009). Affected individuals developed painful skin
lumps in their teenage years. Two family members with mutations had
malignant rhabdoid tumors (609322), and a third was believed to have a
rhabdoid tumor. These 3 patients all died before age 2 year. Two
rhabdoid tumors and several schwannomas showed somatic loss of the
SMARCB1 gene.

Bacci et al. (2010) reported a family in which 4 individuals had
multiple schwannomas and meningiomas. The proband was a 33-year-old man
who had multiple peripheral schwannomas in his legs, first noted at
about age 30. Brain imaging showed an extraaxial mass lesion around the
left hypoglossal foramen, consistent with either a small meningioma or
schwannoma, and spinal imaging showed multiple extraaxial and intradural
mass lesions throughout the spinal cord. He also had multiple
cafe-au-lait spots and painful lumps on the trunk and legs. At age 55,
his father was found to have multiple spinal schwannomas and 2
meningiomas. The proband's paternal aunt had several fibrous
meningiomas, and his cousin had multiple spinal schwannomas. Genetic
analysis identified a heterozygous germline mutation in the SMARCB1 gene
(E31V; 601607.0010) in all patients. Studies of tumor tissue from the
proband showed loss of heterozygosity (LOH) for markers on chromosome 22
including both the SMARCB1 and NF2 genes. Bacci et al. (2010) noted that
meningiomas are not frequently found in patients with schwannomatosis,
but should be considered part of the phenotype.

Christiaans et al. (2011) reported a family in which 5 individuals
developed meningiomas (607174), 2 of whom also developed schwannomas.
All patients carried a heterozygous mutation in the SMARCB1 gene (P48L;
601607.0011), and meningioma tumors showed loss of the wildtype allele,
consistent with the 2-hit hypothesis of tumorigenesis. Meningiomas
developed between ages 34 and 56 years, both in the cranium as
extra-axial lesions and in the spinal cord as extramedullary lesions. In
addition, 1 patient developed multiple chest wall and spinal schwannomas
and another developed a single vestibular schwannoma. Two different
meningioma tumors from the same patient also carried 2 different
heterozygous somatic mutations in the NF2 gene (607379) as well as loss
of heterozygosity at the NF2 locus. Christiaans et al. (2011) concluded
that the SMARCB1 P48L mutation predisposed the carriers to the
development of meningiomas. The mutation may also have predisposed
carriers to schwannomas, implying that meningiomas may be part of the
schwannomatosis tumor spectrum, as suggested by Bacci et al. (2010), but
the schwannomas may also be coincidental findings. The role of the NF2
mutations was uncertain, but may contribute to a 4-hit hypothesis
involving 2 genes. Van den Munckhof et al. (2012) provided further
studies of the family reported by Christiaans et al. (2011).
Reexamination of tumor tissue from 4 meningiomas and 2 schwannomas
showed that all tumors had LOH for both SMARCB1 and NF2, consistent with
a deletion of a segment of chromosome 22 containing these 2 genes. Three
meningiomas and 2 schwannomas were each found to carry somatic mutations
in the NF2 gene. Thus, the genetic changes found in the 2 tumor types
were the same and characteristic for SMARCB1-mutation positive tumors:
retention of the exon 2 mutation, acquisition of an NF2 mutation, and
LOH of the wildtype allele of both genes. In addition, van den Munckhof
et al. (2012) identified 11 more carriers of the P48L mutation in this
family. Eight of these 11 mutation carriers were found to carry 11
lesions suggestive of cranial meningioma and 6 spinal lesions consistent
with meningiomas or schwannomas. Nine (82%) of the 11 cranial
meningiomas were found in the falx cerebri. Van den Munckhof et al.
(2012) concluded that meningiomas should be included in the
schwannomatosis tumor spectrum.

- Distinction from Neurofibromatosis type II

Schwannomas are benign tumors of the peripheral nerve sheath that
usually occur singly in otherwise normal individuals. Multiple
schwannomas in the same individual suggest an underlying tumor
predisposition syndrome. The most common such syndrome is
neurofibromatosis II. The hallmark of NF2 is the development of
bilateral vestibular nerve schwannomas, but two-thirds or more of all
NF2-affected individuals develop schwannomas in other locations, and
dermal schwannomas (or neurilemmomas) may precede vestibular tumors in
NF2-affected children (Evans et al., 1992; Mautner et al., 1993; Parry
et al., 1994). MacCollin et al. (1996) reviewed reports of individuals
with multiple schwannomas who do not show evidence of vestibular
schwannomas, and suggested that schwannomatosis is a clinical entity
distinct from other forms of neurofibromatosis.

Sasaki and Nakajima (1992) described multiple cutaneous neurilemmomas in
an 8-year-old Japanese girl and a 5-year-old Japanese boy. The boy's
father had bilateral acoustic neuromas, suggestive of NF2, and also had
multiple skin tumors that were diagnosed as neurilemmomas
histopathologically. There were no pigmented macules. The multiple skin
tumors had been present in both children since birth. However, Jacoby et
al. (1997) commented that NF2 could not be excluded in these children,
since vestibular schwannoma may not be apparent until adolescence. In
addition, Jacoby et al. (1997) noted that there had been no previous
reports of schwannomatosis meeting their clinical criteria (see
DIAGNOSIS) who had a positive family history of NF2.

Evans et al. (1997) reported 5 families with schwannomatosis inherited
in an autosomal dominant pattern. The phenotype was consistent, with
multiple skin and spinal tumors and relative sparing of the cranium.
Members of a sixth family, who initially appeared to have
schwannomatosis, developed bilateral acoustic neuromas and were later
classified as having NF2. Genetic linkage in 2 large families with
schwannomatosis showed linkage to chromosome 22q12.2 in the region of
the NF2 gene. Evans et al. (1997) noted the difficulty in distinguishing
the 2 disorders and suggested that young patients thought to have
schwannomatosis may have a variant form of NF2.

DIAGNOSIS

The criteria used by Jacoby et al. (1997) for the diagnosis of
schwannomatosis were as follows: 2 or more pathologically proved
schwannomas and lack of radiographic evidence of vestibular nerve tumor
at age more than 18 years was taken as evidence of definite
schwannomatosis. For presumptive or probable schwannomatosis the
criteria were 2 or more pathologically proved schwannomas, without
symptoms of eighth-nerve dysfunction at an age of more than 30 years; or
2 or more pathologically proved schwannomas in an anatomically limited
distribution (single limb or segment of the spine), without symptoms of
eighth-nerve dysfunction at any age.

MAPPING

Because molecular analysis of tumor specimens from affected individuals
in kindreds with familial schwannomatosis revealed a pattern of somatic
NF2 inactivation incompatible with germline NF2 alteration, MacCollin et
al. (2003) performed linkage analysis in 6 families with
schwannomatosis. They obtained a maximum lod score of 6.60 near marker
D22S1174 in the proximal portion of chromosome 22 centromeric to the NF2
gene. MacCollin et al. (2003) concluded that schwannomatosis is a
distinct entity from neurofibromatosis type II, and that the NF2 region
is not the inherited genetic locus responsible for familial
schwannomatosis.

MOLECULAR GENETICS

- Mutations in the SMARCB1 Gene

Since the NF2 locus had been excluded as the germline event underlying
familial schwannomatosis, and the gene placed centromeric to NF2 on
chromosome 22, Hulsebos et al. (2007) investigated the SMARCB1 gene in a
father and daughter with the disorder. Both were found to be
heterozygous for a inactivating germline mutation of this gene
(601607.0005). In 2 of 4 investigated schwannomas from these patients,
inactivation of the wildtype INI1 allele by a second mutation in exon 5
of the gene (601607.0006) or by loss of the gene was found, consistent
with the Knudson 2-hit hypothesis.

Sestini et al. (2008) identified a de novo germline deletion/insertion
in the SMARCB1 gene (601607.0007) in 1 of 21 unrelated patients with
schwannomatosis. Three different tumors derived from this patient showed
the deletion/insertion and a somatic NF2 mutation on the same allele,
but no other SMARCB1 mutations. In addition, 2 of the tumors had somatic
loss of heterozygosity (LOH) encompassing the SMARCB1 and NF2 region.
Sestini et al. (2008) also found somatic mutations in tumor tissues from
3 additional patients who did not have germline mutations. Tumor tissue
from 1 of these patients contained respective somatic mutations in the
SMARCB1 and NF2 genes as well as LOH, indicative of complete monosomy of
chromosome 22q in this tumor. Tumor tissue from a second patient had
somatic mutation in the NF2 gene as well as LOH for chromosome 22q.
Tumor tissue from the third patient had a somatic mutation in the
SMARCB1 gene and LOH for chromosome 22q. Based on these results, Sestini
et al. (2008) postulated that a 4-hit mechanism involving 2 distinct but
linked tumor suppressor genes, SMARCB1 and NF2, may underlie the
development of tumors in a subset of patients with schwannomatosis.
However, given the low frequency of SMARCB1 germline mutations, there
may also be additional loci involved.

In 5 (33.3%) of 15 families with schwannomatosis and 2 (7.1%) of 28
individuals with sporadic schwannomatosis, Hadfield et al. (2008)
identified germline mutations in the SMARCB1 gene (see, e.g.,
601607.0008). In all of these individuals in whom tumor tissue was
available, tumor tissue showed a second hit with loss of SMARCB1. In
addition, all of these patients had biallelic somatic inactivation of
the NF2 gene. Similar to the report of Sestini et al. (2008), the
findings suggested that 4 hits of these 2 genes are usually necessary to
develop schwannomas. Germline SMARCB1 mutations were associated with a
higher number of spinal tumors in patients with a positive family
history (p = 0.004).

- Somatic Mutation in the NF2 Gene

Honda et al. (1995) analyzed the peripheral leukocytes and tissue from
cutaneous neurilemmomas of 7 patients with neurilemmomatosis, using DNA
markers for different regions of chromosome 22. They detected allele
losses in 3 of 7 tumors from 7 patients with a probe for the NF2 region
and the germline mutations in 2 of 3 tumors from the same 3 patients.
They described 2 mutations in the NF2 gene (607379.0017; 607379.0018).
They concluded that neurilemmomatosis is a form of NF2.

Jacoby et al. (1997) undertook a molecular genetic investigation of the
relationship of schwannomatosis to NF2. They examined the NF2 locus in
20 unrelated schwannomatosis patients and their affected relatives.
Tumors from these patients frequently harbored typical truncating
mutations of the NF2 gene and loss of heterozygosity of the surrounding
region of chromosome 22. Surprisingly, unlike patients with NF2, no
heterozygous NF2 gene changes were seen in normal tissues. Examination
of multiple tumors from the same patient revealed that some
schwannomatosis patients were somatic mosaics for NF2 gene changes. In
contrast, other individuals, particularly those with a positive family
history of schwannomatosis, appeared to have an inherited predisposition
to formation of tumors that carry somatic alterations of the NF2 gene.
This tendency was biased toward the occurrence of different mutations in
the same, coinherited allele within a given family, combined with loss
of the trans allele in any given individual. Although the family data
were consistent with linkage of this trait to the NF2 locus, the studies
implied that the primary event in the tumors lay outside the coding
region of the NF2 gene.

In 28 schwannoma tumor specimens from 17 affected individuals in 8
families with familial schwannomatosis, MacCollin et al. (2003)
identified 20 different somatic mutations in the NF2 gene, 18 of which
were truncating mutations. None of the mutations detected in tumor
specimens were detected in the paired blood specimens and no tumor was
found to have 2 mutations in the NF2 gene. In the 6 instances in which
multiple tumors were from the same patient, no 2 tumors shared the same
mutation. Microsatellite analysis showed that all but 4 of the tumors
had loss of heterozygosity for NF2. Ten of 18 tumors had loss of all
markers, consistent with monosomy or mitotic nondisjunction.

- Other Genes

Buckley et al. (2005) investigated the genetic factors underlying the
differences between schwannomatosis and NF2. They comprehensively
profiled the DNA copy number in samples from patients with sporadic and
familial schwannomatosis, patients with NF2, and a large cohort of
normal controls. Using a tiling-path chromosome 22 genomic array, they
identified 2 candidate regions of copy number variation, which were
further characterized by a higher resolution PCR-based array. In DNA
derived from peripheral blood of a schwannomatosis patient and a
sporadic schwannoma sample, they detected rearrangements of the
immunoglobulin lambda (IGLC1; 147220) locus, which were thought not to
be due to a B-cell-specific somatic recombination of IGLC1. Analysis of
normal controls indicated that these IGLC1 rearrangements were
restricted to the schwannomatosis/schwannoma samples. In a second
candidate region spanning the GSTT1 (600436) and CABIN1 (604251) genes,
they observed a frequent copy number polymorphism at the GSTT1 locus.
They also identified missense mutations in the CABIN1 gene that were
specific to samples from schwannomatosis and NF2.

*FIELD* SA
Kaufman et al. (2003)
*FIELD* RF
1. Bacci, C.; Sestini, R.; Provenzano, A.; Paganini, I.; Mancini,
I.; Porfirio, B.; Vivarelli, R.; Genuardi, M.; Papi, L.: Schwannomatosis
associated with multiple meningiomas due to a familial SMARCB1 mutation. Neurogenetics 11:
73-80, 2010.

2. Buckley, P. G.; Mantripragada, K. K.; de Stahl, T. D.; Piotrowski,
A.; Hansson, C. M.; Kiss, H.; Vetrie, D.; Ernberg, I. T.; Nordenskjold,
M.; Bolund, L.; Sainio, M.; Rouleau, G. A.; Niimura, M.; Wallace,
A. J.; Evans, D. G. R.; Grigelionis, G.; Menzel, U.; Dumanski, J.
P.: Identification of genetic aberrations on chromosome 22 outside
the NF2 locus in schwannomatosis and neurofibromatosis type 2. Hum.
Mutat. 26: 540-549, 2005.

3. Christiaans, I.; Kenter, S. B.; Brink, H. C.; van Os, T. A. M.;
Baas, F.; van den Munckhof, P.; Kidd, A. M. J.; Hulsebos, T. J. M.
: Germline SMARCB1 mutation and somatic NF2 mutations in familial
multiple meningiomas. J. Med. Genet. 48: 93-97, 2011.

4. Evans, D. G. R.; Huson, S. M.; Donnai, D.; Neary, W.; Blair, V.;
Newton, V.; Harris, R.: A clinical study of type 2 neurofibromatosis. Quart.
J. Med. 84: 603-618, 1992.

5. Evans, D. G. R.; Mason, S.; Huson, S. M.; Ponder, M.; Harding,
A. E.; Strachan, T.: Spinal and cutaneous schwannomatosis is a variant
form of type 2 neurofibromatosis: a clinical and molecular study. J.
Neurol. Neurosurg. Psychiat. 62: 361-366, 1997.

6. Hadfield, K. D.; Newman, W. G.; Bowers, N. L.; Wallace, A.; Bolger,
C.; Colley, A.; McCann, E.; Trump, D.; Prescott, T.; Evans, D. G.
R.: Molecular characterisation of SMARCB1 and NF2 in familial and
sporadic schwannomatosis. J. Med. Genet. 45: 332-339, 2008. Note:
Erratum: J. Med. Genet. 45: 608 only, 2008.

7. Honda, M.; Arai, E.; Sawada, S.; Ohta, A.; Niimura, M.: Neurofibromatosis
2 and neurilemmomatosis gene are identical. J. Invest. Derm. 104:
74-77, 1995.

8. Hulsebos, T. J. M.; Plomp, A. S.; Wolterman, R. A.; Robanus-Maandag,
E. C.; Baas, F.; Wesseling, P.: Germline mutation of INI1/SMARCB1
in familial schwannomatosis. Am. J. Hum. Genet. 80: 805-810, 2007.

9. Jacoby, L. B.; Jones, D.; Davis, K.; Kronn, D.; Short, M. P.; Gusella,
J.; MacCollin, M.: Molecular analysis of the NF2 tumor-suppressor
gene in schwannomatosis. Am. J. Hum. Genet. 61: 1293-1302, 1997.

10. Kaufman, D. L.; Heinrich, B. S.; Willett, C.; Perry, A.; Finseth,
F.; Sobel, R. A.; MacCollin, M.: Somatic instability of the NF2 gene
in schwannomatosis. Arch. Neurol. 60: 1317-1320, 2003.

11. MacCollin, M.; Willett, C.; Heinrich, B.; Jacoby, L. B.; Acierno,
J. S., Jr.; Perry, A.; Louis, D. N.: Familial schwannomatosis: exclusion
of the NF2 locus as the germline event. Neurology 60: 1968-1974,
2003.

12. MacCollin, M.; Woodfin, W.; Kronn, D.; Short, M. P.: Schwannomatosis:
a clinical and pathologic study. Neurology 46: 1072-1079, 1996.

13. Mautner, V. F.; Tatagiba, M.; Guthoff, R.; Samii, M.; Pulst, S.
M.: Neurofibromatosis 2 in the pediatric age group. Neurosurgery 33:
92-96, 1993.

14. Niimura, M.: Neurofibromatosis. Rinsho Derma 15: 653-663, 1973.

15. Parry, D. M.; Eldridge, R.; Kaiser-Kupfer, M. I.; Bouzas, E. A.;
Pikus, A.; Patronas, N.: Neurofibromatosis 2 (NF2): clinical characteristics
of 63 affected individuals and clinical evidence for heterogeneity. Am.
J. Med. Genet. 52: 450-461, 1994.

16. Sasaki, T.; Nakajima, H.: Congenital neurilemmomatosis. J. Am.
Acad. Derm. 26: 786-787, 1992.

17. Sestini, R.; Bacci, C.; Provenzano, A.; Genuardi, M.; Papi, L.
: Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated
schwannomas. Hum. Mutat. 29: 227-231, 2008.

18. Swensen, J. J.; Keyser, J.; Coffin, C. M.; Biegel, J. A.; Viskochil,
D. H.; Williams, M. S.: Familial occurrence of schwannomas and malignant
rhabdoid tumour associated with a duplication in SMARCB1. J. Med.
Genet. 46: 68-72, 2009.

19. van den Munckhof, P.; Christiaans, I.; Kenter, S. B.; Baas, F.;
Hulsebos, T. J. M.: Germline SMARCB1 mutation predisposes to multiple
meningiomas and schwannomas with preferential location of cranial
meningiomas at the falx cerebri. Neurogenetics 13: 1-7, 2012.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKELETAL:
[Spine];
Schwannomas;
[Limbs];
Schwannomas

SKIN, NAILS, HAIR:
[Skin];
Schwannomas

NEUROLOGIC:
[Central nervous system];
Spinal tumors;
Absence of vestibular schwannomas at age greater than 18 years;
Meningiomas

NEOPLASIA:
Multiple schwannomas;
Meningiomas

MISCELLANEOUS:
Incomplete penetrance;
Variable expressivity;
Germline and somatic mutations contribute to this disorder

MOLECULAR BASIS:
Caused by mutation in the neurofibromin-2 gene (NF2, 607379.0017);
Caused by mutation in the SWI/SNF-related, matrix-associated, actin-dependent
regulator of chromatin, subfamily B, member 1 gene (SMARCB1, 601607.0005)

*FIELD* CN
Cassandra L. Kniffin - updated: 3/1/2010
Cassandra L. Kniffin - updated: 10/2/2008
Cassandra L. Kniffin - revised: 1/30/2003

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 06/20/2012
ckniffin: 3/1/2010
joanna: 10/10/2008
ckniffin: 10/2/2008
ckniffin: 1/30/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 6/20/2012
Cassandra L. Kniffin - updated: 2/23/2011
Cassandra L. Kniffin - updated: 3/1/2010
Cassandra L. Kniffin - updated: 2/13/2009
Cassandra L. Kniffin - updated: 10/2/2008
Cassandra L. Kniffin - updated: 3/6/2008
Victor A. McKusick - updated: 3/27/2007
Victor A. McKusick - updated: 1/6/2006
Cassandra L. Kniffin - updated: 4/2/2003
Cassandra L. Kniffin - reorganized: 2/6/2003
Victor A. McKusick - updated: 2/16/1998

*FIELD* CD
Victor A. McKusick: 6/22/1992

*FIELD* ED
terry: 12/20/2012
carol: 6/21/2012
terry: 6/21/2012
ckniffin: 6/20/2012
carol: 2/24/2011
ckniffin: 2/23/2011
wwang: 3/3/2010
ckniffin: 3/1/2010
wwang: 6/1/2009
ckniffin: 2/13/2009
wwang: 10/8/2008
ckniffin: 10/2/2008
wwang: 3/12/2008
ckniffin: 3/6/2008
alopez: 4/2/2007
terry: 3/27/2007
carol: 4/18/2006
wwang: 1/17/2006
terry: 1/6/2006
ckniffin: 9/5/2003
ckniffin: 4/2/2003
carol: 2/6/2003
ckniffin: 1/30/2003
carol: 1/29/2003
dholmes: 3/10/1998
mark: 2/25/1998
terry: 2/16/1998
mimadm: 12/2/1994
carol: 3/24/1993
carol: 6/22/1992

MIM 607379
*RECORD*
*FIELD* NO
607379
*FIELD* TI
*607379 NEUROFIBROMIN 2; NF2
;;MERLIN;;
SCHWANNOMIN; SCH
*FIELD* TX

DESCRIPTION

Cell-cell contact between normal cultured diploid cells results in
read moreinhibition of proliferation despite the unlimited availability of
nutrients and growth-promoting factors. A similar phenomenon occurs in
vivo in all adult solid tissues. NF2 is a critical regulator of
contact-dependent inhibition of proliferation and functions at the
interface between cell-cell adhesion, transmembrane signaling, and the
actin cytoskeleton (Curto and McClatchey, 2008).

CLONING

Trofatter et al. (1993) identified a candidate gene responsible for
neurofibromatosis II (NF2; 101000). They suggested that it was a tumor
suppressor gene and observed nonoverlapping deletions in DNA from 2
independent NF2 families as well as alterations in the meningiomas from
2 unrelated NF2 patients. The candidate gene encodes a deduced 595-amino
acid protein with striking similarity to several members of the ERM
family of proteins proposed to link cytoskeletal components with
proteins in the cell membrane; these include ezrin (123900), radixin
(179410), and moesin (309845). Because of the resemblance to these 3
proteins (45-47% identity), Trofatter et al. (1993) called the NF2 gene
product merlin. The authors suggested that the NF2 gene may represent a
novel class of tumor suppressor genes.

Rouleau et al. (1993) likewise isolated a gene, which they designated
schwannomin (SCH), bearing homology to erythrocyte protein 4.1 and the
ezrin/moesin/talin family of genes. To isolate the gene, they cloned the
region between 2 flanking polymorphic markers in which they found
several genes. One of the identified genes was the site of germline
mutations in patients with neurofibromatosis II.

By assembling overlapping cDNA fragments, Chang et al. (2002) obtained a
complete NF2 cDNA. Northern blot analysis revealed a major 6.1-kb
transcript expressed ubiquitously and a minor 2.7-kb transcript
expressed in multiple tissues and several human cell lines. Some tissues
also expressed a 3.9-kb transcript. The ratio of expression of the 6.1-
and 2.7-kb transcripts was tissue specific. Chang et al. (2002) found
that NF2 transcription initiates at several possible start sites and
that there are 8 alternatively spliced isoforms. The predominant
isoforms were designated II and I (full length and lacking exon 16,
respectively). The next most frequent isoforms had deletions of exon 2,
exon 3, or both. All other isoforms were expressed at low frequency.
Chang et al. (2002) concluded that use of multiple polyadenylation sites
likely contributes to the complexity of NF2 transcripts.

Chang et al. (2002) analyzed the promoter region of NF2. They identified
a GC-rich region, but no consensus TATA sequence. Using an NF2
promoter-luciferase chimeric plasmid transfected into several cell
lines, they identified a positive cis-acting element within the GC-rich
sequence that could bind SP1 (189906) and GCF (189901), and they
identified a negative regulatory element. By cotransfection in
Drosophila cells, they confirmed that SP1 could activate the NF2
promoter through the GC-rich sequence.

GENE STRUCTURE

Rouleau et al. (1993) and Trofatter et al. (1993) determined that the
NF2 gene contains 17 exons.

MAPPING

The combined use of family linkage studies and tumor deletion mapping by
Wertelecki et al. (1988), Rouleau et al. (1990), Wolff et al. (1992),
and Arai et al. (1992) localized the NF2 gene to chromosome 22q12.2.

Claudio et al. (1994) demonstrated that the mouse homolog of the NF2
gene is located in the proximal region of chromosome 11. The
localization was achieved by analysis of allele distribution in
recombinant inbred strains using a simple sequence repeat polymorphism
in the 3-prime untranslated region of the mouse NF2 cDNA. The region of
chromosome 11 also contains genes for leukemia inhibitory factor (LIF;
159540) and neurofilament heavy chain polypeptide (NFH; 162230), both of
which map to the same region of human chromosome 22 as does NF2.

GENE FUNCTION

Gutmann et al. (1999) studied rat schwannoma cell lines overexpressing
wildtype merlin isoforms and mutant merlin proteins. Overexpression of
wildtype merlin resulted in transient alterations in F-actin
organization, cell spreading, and cell attachment, and in impaired cell
motility as measured in an in vitro motility assay. These effects were
observed only in cells overexpressing a merlin isoform capable of
inhibiting cell growth and not with mutant merlin molecules (harboring
NF2 patient mutations) or a merlin splice variant (isoform II) lacking
growth-inhibitory activity. These data indicated that merlin may
function to maintain normal cytoskeletal organization, and suggested
that its influence on cell growth depends on specific cytoskeletal
rearrangements.

Gutmann et al. (2001) performed a detailed functional analysis of 8
naturally occurring nonconservative missense mutations in the NF2 gene.
The authors analyzed proliferation, actin cytoskeleton-mediated events,
and merlin folding in a regulatable expression system in rat schwannoma
cells. They demonstrated that mutations clustered in the predicted
alpha-helical region did not impair the function of merlin, whereas
those in either the N- or C-terminus of the protein rendered merlin
inactive as a negative growth regulator. The authors suggested that the
key functional domains of merlin may lie within the highly conserved
FERM domain and the unique C terminus of the protein.

Gutmann et al. (2001) stated that the merlin protein functions as a
negative growth regulator. They demonstrated that regulated
overexpression of the hepatocyte growth factor-regulated tyrosine kinase
substrate (HGS, or HRS; 604375) in rat schwannoma cells yielded effects
similar to those seen with overexpression of merlin, including growth
inhibition, decreased motility, and abnormalities in cell spreading. The
HRS binding domain of merlin was mapped to residues 453-557.
Overexpression of C-terminal merlin had no effect on HRS function,
suggesting to the authors that merlin binding to HRS does not negatively
regulate HRS growth suppressor activity, and that merlin and HRS may
regulate cell growth in schwannoma cells through interacting pathways.
Gutmann (2001) reviewed the functions of neurofibromin (613113) and
merlin in tumor suppression and cell-cell signaling, respectively.

Using yeast 2-hybrid interaction cloning, Scoles et al. (2000)
determined that schwannomin interacts with HRS. They demonstrated the
interaction both in vivo, by immunoprecipitation of endogenous HRS with
endogenous schwannomin, and in vitro, with a binding assay using
bacterially purified HRS and schwannomin. The regions of interaction
included schwannomin residues 256-579 and HRS residues from 480 to the
end of either of 2 HRS isoforms. Schwannomin molecules with an L46R,
L360P, L535P, or Q538P missense mutation demonstrated reduced affinity
for HRS binding. Since HRS is associated with early endosomes and may
mediate receptor translocation to the lysosome, the authors used
indirect immunofluorescence to demonstrate that schwannomin and HRS
colocalize at endosomes in STS26T Schwann cells. The authors
hypothesized that schwannomin is involved in HRS-mediated cell
signaling.

Sun et al. (2002) generated a series of HRS truncation mutants to define
the regions required for merlin binding and HRS growth suppression. The
HRS domain required for merlin binding was narrowed to residues 470-497
(which contain the predicted coiled-coil domain), and the major domain
responsible for HRS growth suppression was localized to residues
498-550. Merlin inhibited growth in Hrs +/+ but not Hrs -/- mouse
embryonic fibroblast cells. In contrast, HRS could suppress cell growth
in the absence of Nf2 expression. The authors concluded that merlin
growth suppression requires HRS expression, and that the binding of
merlin to HRS may facilitate its ability to function as a tumor
suppressor.

Using transient transfection methods, Scoles et al. (2002) showed that
both schwannomin and HRS inhibited STAT3 (102582) activation, and that
schwannomin suppressed STAT3 activation mediated by IGF1 (147440)
treatment in a human schwannoma cell line. Schwannomin inhibited STAT3
and STAT5 (601511) phosphorylation in a rat schwannoma cell line.
Schwannomin with the pathogenic missense mutation Q538P (607379.0006)
failed to bind HRS and did not inhibit STAT5 phosphorylation. The
authors hypothesized that schwannomin requires HRS interaction to be
fully functionally active and to inhibit STAT activation.

Scoles et al. (2002) noted that in addition to binding HRS, both of the
major isoforms of schwannomin are involved in homodimerization and
interact with beta II spectrin (182790) and with EIF3S8 (EIF3C; 603916).
Homodimerization and heterodimerization between isoforms occurs through
the C-terminal half, as does interaction between schwannomin and HRS and
beta II spectrin. Interaction with EIF3S8 occurs through the N-terminal
half of schwannomin. Using yeast 2-hybrid assays to characterize further
the effect of missense mutations on these interactions, Scoles et al.
(2002) found that a mutation in the N-terminal half and a mutation in
the C-terminal alpha helix significantly decreased dimerization and
decreased the affinity between schwannomin and all interacting proteins.
Several clinically significant mutations between amino acids 219 and 352
selectively enhanced interactions with their binding partners. Scoles et
al. (2002) also determined that the sites for schwannomin
self-interaction and their binding strengths differ between isoforms 1
and 2.

To elucidate the properties of merlin that are critical for its tumor
suppressor function, Stokowski and Cox (2000) expressed NF2-causing
mutant merlin proteins in mammalian cells. They found that 80% of the
merlin mutants significantly altered cell adhesion by causing cells to
detach from the substratum. They stated that such changes in cell
adhesion may be an initial step in the pathogenesis of NF2. In addition,
they found that 4 missense mutations decreased the binding of merlin to
the ERM-interacting phosphoprotein EBP-50. Some NF2 point mutations
resembled dominant gain-of-function rather than loss-of-function
alleles.

Fernandez-Valle et al. (2002) noted that mice with conditional deletion
of NF2 exon 2 in Schwann cells develop schwannomas, which confirms the
crucial nature of exon 2 for growth control. They found that the
molecular adaptor paxillin (602505) binds directly to schwannomin in
residues 50-70, which are encoded by exon 2. This interaction mediates
the membrane localization of schwannomin to the plasma membrane, where
it associates with beta-1-integrin (ITGB1; 135630) and ERBB2 (164870).
These studies defined a pathogenic mechanism for the development of
neurofibromatosis II in humans with mutations in exon 2 of NF2.

Schulze et al. (2002) used oncoretrovirus-mediated gene transfer of
different merlin constructs to stably reexpress wildtype merlin in
primary cells derived from human schwannomas. Using 2-parameter FACS
analysis, they demonstrated that expression of wildtype merlin in NF2
cells led to significant reduction of proliferation and G0/G1 arrest in
transduced schwannoma cells. In addition, there was increased apoptosis
of schwannoma cells transduced with wildtype merlin. The authors
concluded that merlin may act as a tumor suppressor.

Bashour et al. (2002) observed that schwannoma-derived Schwann cells
exhibited membrane ruffling and aberrant cell spreading when plated onto
laminin (see 150240), indicative of fundamental F-actin cytoskeletal
defects. They found that mutations in NF2 correlate with F-actin
abnormalities. Using a protein transfer technique with primary human
schwannoma cells containing NF2 mutations, they introduced the NF2
protein in an attempt to reverse the cytoskeletal abnormalities. They
found that isoform-1 of merlin, the growth-suppressing isoform, reversed
the abnormal ruffling and cell spreading and restored normal actin
organization. Other isoforms of merlin and merlin containing a point
mutation did not reverse the phenotype.

Gautreau et al. (2002) noted that the N-terminal FERM domain of
schwannomin is implicated in plasma membrane and filamentous actin
binding and that mutations in this domain impair proper folding. They
found that mutations in the FERM domain were unstable both in vivo and
in vitro due to proteasome-mediated degradation. They hypothesized that
loss of schwannomin through degradation could contribute to the
pathophysiology of NF2.

Shaw et al. (2001) concluded that NF2 functions in Rac (see
602048)-dependent signaling. Using electrophoretic mobility shift
assays, they identified Rac-induced phosphorylation sites in NF2. They
observed that expression of activated Rac-induced phosphorylation of the
NF2 serine-518 residue inhibited NF2 self-association and decreased
association of NF2 with the cytoskeleton. Using cell transfections, the
authors showed that NF2 overexpression inhibited Rac-induced signaling
in a phosphorylation-dependent manner. Also, NF2-deficient fibroblasts
exhibited characteristics of cells overexpressing activated alleles of
Rac. Shaw et al. (2001) hypothesized that NF2 functions as a tumor and
metastasis suppressor through its ability to inhibit Rac-dependent
signaling.

Kressel and Schmucker (2002) showed that splicing out of exon 2 leads to
unrestricted entry of merlin into the nucleus, yet skipping of adjacent
exon 3 has no comparable effect. Exon 2 functioned as a cytoplasmic
retention factor and was able to confer sole cytoplasmic localization to
a GFP fusion protein. Merlin's ability to enter the nucleus is
complemented by a nuclear-cytoplasmic shuttle protein sequence within
exon 15 that facilitates export via the CRM1/exportin pathway. The
authors proposed a cellular function different to the wildtype protein
for naturally occurring splice variants lacking exon 2.

Jin et al. (2006) identified MYPT1 (602021) as the enzyme that activates
the tumor suppressor function of merlin. The cellular MYPT1-PP1-delta
(600590)-specific inhibitor CPI17 (608153) caused a loss of merlin
function characterized by merlin phosphorylation, Ras activation, and
transformation. Constitutively active merlin containing the mutation
S518A reversed CPI17-induced transformation, showing that merlin is the
decisive substrate of MYPT1-PP1-delta in tumor suppression. In addition,
Jin et al. (2006) showed that CPI17 levels are raised in several human
tumor cell lines and that the downregulation of CPI17 induces merlin
dephosphorylation, inhibits Ras activation, and abolishes the
transformed phenotype. Jin et al. (2006) concluded that MYPT1 and its
substrate merlin are part of a previously undescribed tumor suppressor
cascade that can be hindered in 2 ways, by mutation of the NF2 gene and
by upregulation of the oncoprotein CPI17.

By reciprocal yeast 2-hybrid and coimmunoprecipitation analyses of the
human STS26T malignant schwannoma cell line, Scoles et al. (2006) showed
that isoforms 1 and 2 of schwannomin interacted with EIF3C, a subunit of
eukaryotic initiation factor-3 (EIF3). Mutation analysis revealed that
the FERM domain of schwannomin interacted with the C-terminal half of
EIF3C. Immunofluorescence microscopy of STS26T cells showed that the 2
proteins partly colocalized at punctate perinuclear structures and at
some membranous structures. Overexpression of EIF3C in STS26T cells
elevated cell proliferation, and schwannomin countered this effect.
Western blot analysis revealed an inverse abundance of schwannomin and
EIF3C in human meningiomas. Scoles et al. (2006) concluded that
schwannomin functions as a tumor suppressor by inhibiting EIF3-mediated
initiation of protein translation.

Curto and McClatchey (2008) reviewed the mechanisms by which NF2
regulates contact-dependent inhibition of proliferation.

MOLECULAR GENETICS

Rouleau et al. (1993) provided incontrovertible evidence that the NF2
gene is the site of the mutations causing neurofibromatosis II (101000)
by demonstrating germline and somatic SCH mutations in NF2 patients and
in NF2-related tumors. They found 16 mutations, 15 of which were
predicted to result in truncated proteins (see 607379.0001 and
607379.0002). Consistent with the classic Knudson theory of tumor
suppressor genes, loss of the wildtype allele at the NF2 locus was
demonstrated in 6 of 8 tumors containing NF2 mutations (Trofatter et
al., 1993; Rouleau et al., 1993). For example, in a meningioma in a
patient without features of NF2, they found deletion of 2 nucleotides,
TC, from codon 61 resulting in a frameshift; the normal allele on the
other chromosome had been lost. In 2 instances of schwannoma occurring
in patients without evidence of NF2, Rouleau et al. (1993) found
nonsense mutations that were absent in the patient's blood DNA; in these
instances also the normal allele had been lost.

Most of the mutations in NF2 cause the synthesis of a truncated
schwannomin protein. After examining 8 of the 16 known NF2 exons in 151
meningiomas, Ruttledge et al. (1994) characterized 24 inactivating
mutations. Significantly, these aberrations were detected exclusively in
tumors that had lost the other chromosome 22 allele. These results
provided strong evidence that the suppressor gene on chromosome 22,
frequently inactivated in meningioma, is the NF2 gene. The same group
had found loss of heterozygosity (LOH) for polymorphic DNA markers
flanking NF2 on chromosome 22 in 102 (60%) of 170 primary sporadic
meningiomas. Thus, another gene may be involved in the development of
40% of meningiomas. All 24 of the inactivating mutations found by
Ruttledge et al. (1994) in sporadic meningiomas were nonsense,
frameshift (due to small deletions), or splice site mutations; there
were no missense mutations.

Sainz et al. (1994) performed mutation analysis in 30 vestibular
schwannomas and found 18 mutations in NF2, 7 of which contained loss or
mutation of both alleles. Most mutations predicted a truncated protein.
Mutation hotspots were not identified. Only 1 of the mutations was in a
tumor from a patient with NF2. Immunocytochemical studies using
antibodies to the NF2 protein showed complete absence of staining in
tumor Schwann cells, whereas staining was observed in normal vestibular
nerve. These data indicated that loss of NF2 protein function is a
necessary step in schwannoma pathogenesis and that the NF2 gene
functions as a recessive tumor suppressor gene. In studies of 34
vestibular schwannomas and 14 schwannomas at other locations, Bijlsma et
al. (1994) found that the SCH gene is implicated in the development of
these tumors in all locations of the nervous system.

Bianchi et al. (1994) described a novel isoform of the NF2 transcript
that shows differential tissue expression and encodes a modified C
terminus of the predicted protein. Mutations affecting both isoforms of
the NF2 transcript were detected in multiple tumor types including
melanoma and breast carcinoma. These findings provided evidence that
alterations in the NF2 transcript occurred not only in the hereditary
brain neoplasms typically associated with NF, but also as somatic
mutations in their sporadic counterparts and in seemingly unrelated
tumor types.

Using a screening method based on denaturing gradient gel
electrophoresis, which allows the detection of mutations in 95% of the
coding sequence, Merel et al. (1995) observed mutations in 17 of 57
meningiomas and in 30 of 89 schwannomas. All of the meningiomas and half
of the schwannomas with identified NF2 mutations demonstrated chromosome
22 allelic losses. No mutations were observed in 17 ependymomas, 70
gliomas, 23 primary melanomas, 24 pheochromocytomas, 15 neuroblastomas,
6 medulloblastomas, 15 colon cancers, and 15 breast cancers. This led
Merel et al. (1995) to conclude that the involvement of the NF2 gene is
restricted to schwannomas and meningiomas, where it is frequently
inactivated by a 2-hit process.

Wellenreuther et al. (1995) likewise concluded that NF2 represents the
meningioma locus on chromosome 22. There was a significant association
of loss of heterozygosity on chromosome 22 with mutations in the NF2
gene. They analyzed the entire coding region of the NF2 gene in 70
sporadic meningiomas and identified 43 mutations in 41 patients. These
resulted predominantly in immediate truncation, splicing abnormalities,
or an altered reading frame of the predicted protein product. All
mutations occurred in the first 13 exons, the region of homology with
the filopodial proteins moesin, ezrin, and radixin.

Zucman-Rossi et al. (1998) noted that although penetrance of
neurofibromatosis II is greater than 95% and no genetic heterogeneity
has been described, point mutations in the NF2 gene have been observed
in only 34 to 66% of screened NF2 patients in various series. They
deduced the entire genomic sequence of the NF2 gene and undertook a
mutation screening strategy that, when applied to a series of 19 NF2
patients, revealed a high recurrence of large deletions in the gene and
raised the efficiency of mutation detection in NF2 patients to 84% of
the cases in this series. The remaining 3 patients who expressed 2
functional NF2 alleles were all sporadic cases, an observation
compatible with the presence of mosaicism for NF2 mutations.

Legoix et al. (1999) estimated that about 50% of NF2 patients show point
mutations in the NF2 gene, and that large genomic deletions account for
approximately one-third of NF2 gene alterations. To facilitate deletion
screening, they identified 16 polymorphic markers in the NF2 genomic
sequence, enabling a hemizygosity test in familial studies.

Kluwe et al. (2000) studied 40 skin tumors (36 schwannomas and 4
neurofibromas) from 20 NF2 patients, 15 of whom had NF2 mutations
previously identified in blood leukocytes. The detection rate of
constitutional mutations was higher in patients with skin tumors (65%)
than in patients without skin tumors (40%). They found NF2 mutations in
5 tumors (13%) and NF2 allelic loss in 18 (45%) of the 40 examined
tumors. Alterations in both NF2 alleles were found in 17 (43%) of the
tumors. They concluded that loss of a functional NF2 gene product is a
critical event in the generation of skin schwannomas and that mutation
detection in skin tumors may be a useful diagnostic tool in patients
with skin tumors where the clinical diagnosis of NF2 is ambiguous, or in
unclear cases in which NF1 must be excluded.

Tsilchorozidou et al. (2004) reported 5 NF2 patients with constitutional
rearrangements of chromosome 22 and vestibular schwannomas, multiple
intracranial meningiomas, and spinal tumors. The authors noted that an
additional 10 NF2 patients with constitutional NF2 deletions had been
discovered using NF2 FISH in their laboratory, and suggested that
chromosome analysis with FISH might be a useful first screen prior to
molecular testing in NF2 patients.

Kluwe et al. (2000) studied 71 sporadic NF2 patients using both LOH and
pedigree analysis and compared the parental origin of the new mutation
with the underlying molecular change. In 45 informative individuals, 31
mutations (69%) were of paternal origin and 14 (31%) of maternal origin.
In 4 of 6 patients with somatic mosaicism, the NF2 mutation was of
maternal origin.

Ahronowitz et al. (2007) presented a metaanalysis of 967 constitutional
and somatic NF2 alterations from 93 published reports, along with 59
additional unpublished mutations identified in their laboratory and 115
alterations identified in clinical samples submitted to the
Neurogenetics DNA Diagnostic Laboratory of the Massachusetts General
Hospital. In total, these sources defined 1,070 small genetic changes
detected primarily by exon scanning, 42 intragenic changes of 1 whole
exon or larger, and 29 whole gene deletions and gross chromosomal
rearrangements. Overall, somatic events showed a significantly different
genetic profile than constitutional events. Somatic events were strongly
skewed toward frameshift (accounting for over one-half of these
mutations) in comparison to constitutional changes that were primarily
nonsense and splice site, as had been previously described by Baser and
Contributors to the International NF2 Mutation Database (2006). Somatic
events also differed markedly between tumors of different pathology,
most significantly in the tendency of somatic events in meningiomas to
lie within the 5-prime FERM domain of the transcript with a complete
absence of mutations in exons 14 and 15. Less than 10% of all published
and unpublished small alterations were nontruncating and these changes
were clustered in exons 2 and 3, suggesting that this region may be
especially crucial to tumor suppressor activity in the protein.

- Somatic Mosaicism

Evans et al. (1998) sought mutations in the NF2 gene in 125 families
with classic NF2 with bilateral vestibular schwannomas; causative
mutations were identified in 52 families. In 5 families, the first
affected individual in the family was a mosaic for a disease-causing
mutation. Only 1 of the 9 children from the 3 mosaic cases with children
were affected. Four of these 9 children inherited the allele associated
with the disease-causing mutation yet did not inherit the mutation. NF2
mutations were identified in only 27 of 79 (34%) sporadic cases,
compared with 25 of 46 (54%) familial cases (P less than 0.05). In 48
families in which a mutation had not been identified, the index cases
had 125 children, of whom only 29 were affected with NF2 and of whom
only a further 21 cases would be predicted to be affected by use of life
curves. The 50 of 125 (40%) cases is significantly less than the 50%
expected eventually to develop NF2 (P less than 0.05). Somatic mosaicism
is likely to be a common cause of classic NF2 and may well account for a
low detection rate for mutations in sporadic cases. Degrees of gonosomal
mosaicism mean that recurrence risks may well be less than 50% in the
offspring of the index case when a mutation was not identified in
lymphocyte DNA.

Kluwe and Mautner (1998) concluded that mosaicism is relatively common
in NF2, with important implications for diagnosis, prognosis, and
genetic counseling. In 4 sporadic NF2 patients, they found NF2 mutations
in only a portion of leukocytes. In 2 other sporadic patients, no
mutations were found in leukocytes but constitutional NF2 mutations were
suggested by the finding of identical mutations in different tumors from
each patient. Kluwe and Mautner (1998) screened leukocyte DNA from a
total of 16 inherited and 91 sporadic NF2 patients, and found NF2
mutations in 13 (81%) of the former and in 46 (51%) of the latter cases.
They suspected that the 30% difference in the rate of detection of
mutations might be partially explained by mosaicism in a portion of
sporadic NF2 patients who carry the mutations in such a fashion that
their leukocytes are unaffected. Among sporadic cases, they found
mutations to be more frequent in patients with severe phenotypes (59%)
than in patients with mild phenotypes (23%). This likewise might be
explained by mosaicism, with the smaller population of mutation-bearing
cells resulting in mild phenotypes. No mutations were found in 8
patients suspected of having NF2.

Sestini et al. (2000) reported the genetic study of 33 NF2 patients from
33 unrelated Italian families. Twelve mutations were characterized,
including 7 newly identified mutations and 5 recurrent ones.
Furthermore, they described 1 patient with an inactivating mutation in
exon 13 present in only a portion of the lymphocytes and, more
importantly, a clinically normal individual carrying a somatic/germinal
mosaicism for a nonsense mutation in exon 10 of the NF2 gene. The
results confirmed the relatively high percentage of mosaicism for
mutations in the NF2 gene and established the importance of evaluating
genomic DNA from several tissues, in addition to lymphocytes, so as to
identify mosaicism in 'de novo' NF2 patients and their relatives.

Moyhuddin et al. (2003) described mutation analysis of 27 mosaic cases
of NF2 and the results of genetic testing in their children. They
estimated that 30% of de novo NF2 patients are mosaic. The authors
suggested that mosaicism should be suspected in a mildly affected
isolated patient with no mutation detected in blood. Risk of
transmission to offspring is small in an NF2 patient with a mutation
detectable only in tumor.

Kluwe et al. (2003) identified mutations in the NF2 gene in peripheral
blood of 122 of 233 (52%) NF2 founders (those with clinically unaffected
parents). Mutations in the NF2 gene were identified in 21 of 35
available tumor specimens from the 111 patients who did not have
detectable peripheral blood mutations. Nine of these patients had a
constitutional mutation which was also found in distinct second tumors.
Kluwe et al. (2003) concluded that failure to find NF2 mutations in
peripheral blood of NF2 mutations was due to somatic mosaicism. By
extrapolation, the authors estimated that the rate of somatic mosaicism
in their cohort was 24.8%.

- Schwannomatosis

Neurilemmomatosis (162091), also called schwannomatosis, first reported
by Niimura (1973) as neurofibromatosis type 3, is characterized by
multiple cutaneous neurilemmomas and spinal schwannomas, without
acoustic tumors or other signs of NF1 or NF2. In neurilemmomas, the
tumor consists of Schwann cells. Honda et al. (1995) analyzed the
peripheral leukocytes and tissue from cutaneous neurilemmomas of 7
patients with neurilemmomatosis using DNA markers for different regions
of chromosome 22. They detected allele losses in 3 of 7 tumors from 7
patients with a probe for the NF2 region and the germline mutations in 2
of 3 tumors from the same 3 patients. They described 2 mutations in the
NF2 gene (607379.0017; 607379.0018). They concluded that
neurilemmomatosis is a form of NF2.

Jacoby et al. (1997) investigated the molecular genetic basis of
schwannomatosis in patients with multiple schwannomas without vestibular
schwannomas, which has been postulated to represent a distinct subclass
of neurofibromatosis. They found the unusual situation that in studies
of 20 unrelated schwannomatosis patients and their affected relatives,
tumors from the patients frequently harbored typical truncating
mutations of the NF2 gene and loss of heterozygosity of the surrounding
region of chromosome 22. Surprisingly, unlike patients with NF2, no
heterozygous NF2 gene changes were seen in normal tissues. Furthermore,
examination of multiple tumors from the same patients revealed that some
schwannomatosis patients are somatic mosaics for NF2 gene changes. By
contrast, other individuals, particularly those with a positive family
history, appeared to have an inherited predisposition to formation of
tumors that carry somatic alterations of the NF2 gene.

In 7 tumor specimens resected from a 36-year-old man with
schwannomatosis, Kaufman et al. (2003) found LOH at the NF2 locus in all
tumors, and in every case the same allele was lost, implying that
somatic mutations accumulate on the same retained allele. Four of the
specimens contained unrelated truncating mutations of the NF2 gene.

Sestini et al. (2008) identified somatic mutations in the NF2 gene in
tumor tissue derived from 3 unrelated patients with schwannomatosis. LOH
was also observed in all cases.

- Malignant Mesothelioma

Malignant mesotheliomas (MMs; 156240) are aggressive tumors that develop
most frequently in the pleura of patients exposed to asbestos. In
contrast to many other cancers, relatively few molecular alterations had
been described in MMs. The most frequent numerical cytogenetic
abnormality in MMs is loss of chromosome 22. This prompted Bianchi et
al. (1995) to investigate the status of the NF2 gene in these tumors. In
studies of cDNAs from 15 MM cell lines and genomic DNAs from 7 matched
primary tumors, NF2 mutations predicting either interstitial in-frame
deletions or truncation of the NF2-encoded protein (merlin) were
detected in 8 cell lines (53%), 6 of which were confirmed in primary
tumor DNAs. In 2 samples that showed NF2 gene transcript alterations, no
genomic DNA mutations were detected, suggesting that aberrant splicing
may constitute an additional mechanism for merlin inactivation. Unlike
previously described NF2-related tumors, MM derived from the mesoderm;
malignancies of this origin had not previously been associated with
frequent alterations of the NF2 gene. In a commentary in the same
journal issue, Knudson (1995) wrote: 'We are left wondering why
mesothelioma is not a feature of the hereditary disease NF2.' Baser et
al. (2002) reported a patient with NF2 who developed malignant
mesothelioma after a long occupational exposure to asbestos. Genetic
analysis of the tumor tissue showed loss not only of chromosome 22 but
also of chromosomes 14 and 15, and gain of chromosome 7. Baser et al.
(2002) suggested that an individual with a constitutional mutation of an
NF2 allele, as in NF2, is more susceptible to mesothelioma. Although
mesothelioma is not a common feature in NF2, the authors cited the
observation of Knudson (1995) that somatic mutations of a tumor
suppressor gene, such as NF2, RB1 (614041), or p53 (191170), can be
common in a tumor type that is not characteristic of the hereditary
disorder, perhaps due to the proliferative timing of the cells involved.

Fleury-Feith et al. (2003) noted that biallelic NF2 gene inactivation is
frequently found in human malignant mesothelioma. To assess whether NF2
hemizygosity may enhance susceptibility to asbestos fibers, they
investigated the NF2 status in mesothelioma developed in mice presenting
a heterozygous mutation of the Nf2 gene, after intraperitoneal
inoculation of crocidolite fibers. Asbestos-exposed mice heterozygous
for a knockout of Nf2 developed tumoral ascites and mesothelioma at
higher frequency than their wildtype counterparts (P less than 0.05).
Six out of 7 mesothelioma cell lines established from neoplastic ascitic
fluids of these heterozygous knockout mice exhibited loss of the
wildtype Nf2 allele and no neurofibromatosis type 2 protein expression
was found in these cells. The results showed the importance of the Nf2
gene in mesothelial oncogenesis, the potential association of asbestos
exposure and tumor suppressor gene inactivation, and suggested that NF2
gene mutation may be a susceptibility factor to asbestos.

GENOTYPE/PHENOTYPE CORRELATIONS

Parry et al. (1996) used SSCP analysis to screen for mutations in DNA
from 32 unrelated NF2 patients. Mutations were identified in 66% of
patients and 20 different mutations were found in 21 patients. They
suggested that their results confirmed the association between nonsense
and frameshift mutations and clinical manifestations compatible with
severe disease. They stated that their data raised questions regarding
the role of other factors, in addition to the intrinsic properties of
individual mutations, that might influence the phenotype. Ruttledge et
al. (1996) reported that when individuals harboring protein-truncating
mutations are compared with patients having single codon alterations, a
significant correlation (p less than 0.001) with clinical outcome is
observed. They noted that 24 of 28 patients with mutations that cause
premature truncation of the NF2 protein presented with severe
phenotypes. In contrast, all 16 cases from 3 families with mutations
that affect only a single amino acid had mild NF2.

Evans et al. (1998) reported 42 cases of NF2 from 38 families with
truncating mutations. The average age of onset of symptoms was 19 years
and age at diagnosis 22.4 years. Fifty-one cases from 16 families (15
with splice site mutations, 18 with missense mutations, and 18 with
large deletions) had an average age of onset of 27.8 years and age at
diagnosis of 33.4 years. Subjects with truncating mutations were
significantly more likely to develop symptoms before 20 years of age (p
less than 0.001) and to develop at least 2 symptomatic CNS tumors in
addition to vestibular schwannoma before 30 years (p less than 0.001).
There were significantly fewer multigenerational families with
truncating mutations.

Kehrer-Sawatzki et al. (1997) reported a patient with NF2 and a ring
chromosome 22 (46,XX,r(22)/45,XX,-22). Severe manifestations included
multiple meningiomas, spinal and peripheral neurinomas, and bilateral
vestibular schwannomas. The patient was also severely mentally retarded,
a feature not usually associated with NF2. The authors hypothesized that
a mutation in the NF2 gene of the normal chromosome 22, in addition to
the loss of the ring 22 in many cells during mitosis, could explain the
presence of multiple tumors. Using a meningioma cell line lacking the
ring chromosome, Kehrer-Sawatzki et al. (1997) searched for deletions,
rearrangements, or other mutations of the NF2 gene on the normal
chromosome 22; no such alterations were found. The authors concluded
that the loss of the entire chromosome 22 and its multiple tumor
suppressor genes may have led to the severe phenotype in this patient.

Bruder et al. (2001) examined the 7-Mb interval in the vicinity of the
NF2 gene in a series of 116 NF2 patients in order to determine the
frequency and extent of deletions. Using high-resolution
array-comparative genomic hybridization (CGH) on an array covering at
least 90% of the region around the NF2 locus, deletions of various sizes
were detected in 8 severe, 10 moderate, and 6 mild patients. This result
did not support a correlation between the type of mutation affecting the
NF2 gene and the disease phenotype.

In 831 patients from 528 NF2 families, Baser et al. (2005) analyzed
location of splice site mutations and severity of NF2, using age at
onset of symptoms and number of intracranial meningiomas as indicators.
They found that individuals with splice site mutations in exons 1 to 5
had more severe disease than those with splice site mutations in exons
11 to 15. Baser et al. (2005) confirmed the previously reported
observation that missense mutations are usually associated with mild
NF2.

Constitutional heterozygous inactivating mutations in the NF2 gene cause
the autosomal dominant disease neurofibromatosis type 2, whereas
biallelic inactivating somatic NF2 mutations are found in a high
proportion of unilateral sporadic vestibular schwannomas (USVSs) and
sporadic meningiomas. Baser and Contributors to the International NF2
Mutation Database (2006) surveyed the distributions of constitutional
NF2 mutations in 823 NF2 families, 278 somatic NF2 mutations in USVS,
and 208 somatic NF2 mutations in sporadic meningioma. Based on the
available NF2 mutation data, the most dominant influence on the spectra
of mutations in exon 1 through 15 were found to be C-to-T transitions
that change arginine codons (CGA) to stop codons (TGA) due to
spontaneous deamination of methylcytosine to thymine in CpG
dinucleotides. The paucity of reported mutations in exon 9 and the
absence of reported mutations in exons 16 and 17 may be related to
structure-function relationships in the NF2 protein.

ANIMAL MODEL

Hemizygosity for the NF2 gene in humans causes a syndromic
susceptibility to schwannoma. However, Nf2 hemizygous mice do not
develop schwannomas but mainly osteosarcomas. In the tumors of both
species, the second Nf2 allele is inactivated. Giovannini et al. (2000)
reported that conditional homozygous Nf2 knockout mice with Cre-mediated
excision of Nf2 exon 2 in Schwann cells showed characteristics of human
NF2, including schwannomas, Schwann cell hyperplasia, cataract, and
osseous metaplasia. Thus, the tumor suppressor function of Nf2, revealed
in murine Schwann cells, was concealed in hemizygous Nf2 mice because of
insufficient rate of second allele inactivation in this cell
compartment.

*FIELD* AV
.0001
NEUROFIBROMATOSIS, TYPE II
NF2, LEU360PRO

After isolating a candidate gene for neurofibromatosis type 2 (101000)
by cloning the region of chromosome 22 between 2 flanking markers,
Rouleau et al. (1993) succeeded in demonstrating that the gene is indeed
the site of germline mutations in NF2 patients and of somatic mutations
in NF2-related tumors. The search was initiated by first determining the
exons and intron-exon boundaries within the coding sequence of the gene
they referred to as schwannomin (SCH). Specific exons were amplified by
polymerase chain reaction (PCR) and the resulting products were analyzed
using denaturing gradient gel electrophoresis as described by Myers et
al. (1985). A total of 15 genetic variants were identified. With the
exception of a leu360-to-pro mutation due to a T-to-C transition, all
the variants were nonsense, frameshift, or splice mutations predicted to
lead to the synthesis of a truncated SCH protein. Whenever it was
possible to investigate several family members in 2 generations, the SCH
mutations were found to segregate with the disease. In 3 instances, the
DNA variants were present only in the patient's constitutional DNA and
not in either of the unaffected parents, providing strong evidence for a
causal relationship between the occurrence of a new mutation and the
development of the disease.

.0002
NEUROFIBROMATOSIS, TYPE II
NF2, IVS2, G-T, +1

In a patient with hereditary neurofibromatosis type II (101000), Rouleau
et al. (1993) identified a change from AGgt to AGtt at the junction
between codons 80 and 81 (presumably the splice donor site of intron 2).

.0003
MENINGIOMA, SOMATIC
NF2, 1-BP DEL, 993A

Among the 24 inactivating mutations in the NF2 gene found by Ruttledge
et al. (1994) in sporadic meningiomas (607174) were 7 instances of
deletion of 1 bp. One of these was deletion of adenine at position 993
resulting in frameshift. An LOH pattern consistent with monosomy for
chromosome 22, i.e., loss of the homologous NF2 locus, was found in this
as well as in most of the other 23 tumors.

.0004
MENINGIOMA, SOMATIC
NF2, ARG57TER

Papi et al. (1995) analyzed 61 sporadic meningiomas (607174) for loss of
heterozygosity of 22q and for mutations in the NF2 gene. LOH was
detected in 36 of the 60 informative tumors. They used single-strand
conformation analysis to identify 9 mutations in 5 of the 8 exons of the
NF2 gene studied. The 9 tumors with an altered NF2 gene also showed LOH
for 22q markers, supporting the hypothesis that the NF2 gene acts as a
tumor suppressor. Papi et al. (1995) found no germline mutations in
these cases. One of the fibroblastic meningiomas in a 62-year-old female
had a C-to-T transition at codon 57 in exon 2, resulting in a premature
stop codon.

.0005
NEUROFIBROMATOSIS, TYPE II
NF2, LEU535PRO

Evans et al. (1995) reported a family with type II neurofibromatosis
(101000) and late-onset tumors. Hearing loss developed late in life in 5
members of the family, 2 of whom were first shown to have NF2 in their
70s. Three other obligate gene carriers died undiagnosed at ages 64, 72,
and 78 years of age. Evans et al. (1995) demonstrated a missense
mutation at the C-terminal end of the NF2 protein; a T-to-C transition
at nucleotide 1604 caused a leu535-to-pro amino acid substitution.

.0006
NEUROFIBROMATOSIS, TYPE II
NF2, GLN538PRO

In a family in which 4 members were affected with NF2 (101000), Kluwe
and Mautner (1996) found a gln538-to-pro mutation in exon 15 of the NF2
gene by studying lymphocyte DNA. They suggested that missense mutations
such as this were rare. Although both of the 2 affected members of the
family who were studied developed bilateral vestibular schwannomas, the
first showed onset of the disease at the age of 31 years and presented
with various central, peripheral, and abdominal tumors, while the second
patient showed later onset of clinical symptoms (at age 52 years) and
presented with only 2 additional small spinal tumors.

.0007
NEUROFIBROMATOSIS, TYPE II
NF2, PHE96DEL

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified an in-frame deletion of 3 basepairs corresponding to
codon 96 (CTT) in exon 3. The mutation causes a deletion of
phenylalanine at position 96.

.0008
NEUROFIBROMATOSIS, TYPE II
NF2, GLU182TER

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified a G-to-T substitution at nucleotide 544 in exon 6,
resulting in a stop codon at position 182.

.0009
NEUROFIBROMATOSIS, TYPE II
NF2, ARG262TER

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified a C-to-T substitution at nucleotide 784 in exon 8,
resulting in a stop codon at position 262.

.0010
NEUROFIBROMATOSIS, TYPE II
NF2, GLN320TER

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified a C-to-T substitution at nucleotide 958 in exon 10,
resulting in a stop codon at position 320.

.0011
NEUROFIBROMATOSIS, TYPE II
NF2, ARG341TER

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified a C-to-T substitution at nucleotide 1021 in exon 11,
resulting in a stop codon at position 341.

.0012
NEUROFIBROMATOSIS, TYPE II
NF2, GLN407TER

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified a C-to-T substitution at nucleotide 1219 in exon 12,
resulting in a stop codon at position 407.

.0013
NEUROFIBROMATOSIS, TYPE II
NF2, GLU463TER

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified a G-to-T substitution at nucleotide 1387 in exon 13,
resulting in a stop codon at position 463.

.0014
NEUROFIBROMATOSIS, TYPE II
NF2, ARG466TER

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified a C-to-T substitution at nucleotide 1396 in exon 13,
resulting in a stop codon at position 466.

.0015
NEUROFIBROMATOSIS, TYPE II
NF2, GLU527TER

In a study of 33 unrelated patients with NF2 (101000), MacCollin et al.
(1994) identified a G-to-T substitution at nucleotide 1579 in exon 15,
resulting in a stop codon at position 527.

.0016
NEUROFIBROMATOSIS, TYPE II
NF2, PHE62SER

Scoles et al. (1996) found a T-to-C transition at nucleotide 185 in exon
2 resulting in a substitution of serine for phenylalanine-62 in a family
with both mild and severe NF2 (101000) phenotypes. This mutation had
previously been reported by Bourn et al. (1994) in a family in which the
NF2 phenotype was uniformly mild.

Paxillin (602505) is an adaptor protein that integrates adhesion- and
growth factor-dependent signals with changes in actin organization and
gene expression. Paxillin contains several protein-protein binding
motifs. Fernandez-Valle et al. (2002) showed that the molecular adaptor
paxillin binds directly to schwannomin at residues 50-70, which are
encoded by exon 2. This interaction mediates the membrane localization
of schwannomin to the plasma membrane, where it associates with
beta-1-integrin (135630) and ERBB2 (164870). The work defined a
pathogenic mechanism for the development of NF2 in humans with mutations
in exon 2 of NF2.

.0017
SCHWANNOMATOSIS, SOMATIC
NF2, 245-BP DEL

In a study involving 7 neurilemmomatosis (162091) patients, Honda et al.
(1995) analyzed peripheral leukocytes and tissue from cutaneous
neurilemmomas and found a deletion from codon 334 to at least 579 in the
NF2 gene. The authors considered this finding, along with that described
in 607379.0018, sufficient to suggest that neurilemmomatosis is in fact
a form of NF2.

.0018
SCHWANNOMATOSIS, SOMATIC
NF2, 1-BP INS

See 607379.0017. Honda et al. (1995) found a G insertion at codon 42 of
the NF2 gene, resulting in a frameshift.

.0019
SCHWANNOMATOSIS, SOMATIC
NF2, 7-BP DEL, NT105

In a patient with neurilemmomatosis (162091), a 52-year-old man with
bilateral multiple schwannomas in the legs (pain in the left leg began
at the age of 45 years), Jacoby et al. (1997) found deletion of
nucleotides 205 to 211 in exon 2 of the NF2 gene. This produced a
frameshift beginning at lysine-69 and leading to premature termination
at codon 122. The mutation was somatic in origin inasmuch as other body
cells did not show the mutation. This was despite the fact that the
father and a niece were said to be affected also. Two other tumors
showed different somatic mutations, one a frameshift mutation in exon 5
of NF2 and another a different frameshift mutation in exon 2. Loss of
heterozygosity for markers in the region of chromosome 22 surrounding
the NF2 gene was found in all 3 tumors. This and similar findings in
other cases suggested to Jacoby et al. (1997) the existence of an
inherited predisposition to the formation of tumors that carry somatic
alterations of the NF2 gene.

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*FIELD* CN
Patricia A. Hartz - updated: 4/28/2011
Patricia A. Hartz - updated: 2/23/2009
Cassandra L. Kniffin - updated: 3/6/2008
Victor A. McKusick - updated: 3/21/2007
Ada Hamosh - updated: 9/8/2006
Victor A. McKusick - updated: 6/6/2006
Marla J. F. O'Neill - updated: 9/19/2005
Cassandra L. Kniffin - updated: 10/21/2004
George E. Tiller - updated: 9/2/2004
Marla J. F. O'Neill - updated: 8/27/2004
Victor A. McKusick - updated: 2/2/2004
George E. Tiller - updated: 10/13/2003
Victor A. McKusick - updated: 9/4/2003
Dawn Watkins-Chow - updated: 4/7/2003

*FIELD* CD
Cassandra L. Kniffin: 11/25/2002

*FIELD* ED
tpirozzi: 10/01/2013
carol: 8/5/2013
alopez: 3/14/2013
alopez: 6/17/2011
mgross: 5/19/2011
terry: 4/28/2011
joanna: 11/23/2009
mgross: 2/24/2009
terry: 2/23/2009
wwang: 3/12/2008
ckniffin: 3/6/2008
alopez: 3/21/2007
alopez: 9/11/2006
terry: 9/8/2006
alopez: 6/12/2006
terry: 6/6/2006
wwang: 10/4/2005
terry: 9/19/2005
carol: 12/28/2004
ckniffin: 10/21/2004
carol: 9/3/2004
terry: 9/2/2004
carol: 8/27/2004
terry: 8/27/2004
carol: 2/12/2004
tkritzer: 2/3/2004
tkritzer: 2/2/2004
tkritzer: 1/23/2004
ckniffin: 1/21/2004
cwells: 10/13/2003
cwells: 9/8/2003
terry: 9/4/2003
cwells: 4/7/2003
carol: 1/29/2003
carol: 1/28/2003
ckniffin: 1/13/2003
ckniffin: 1/10/2003