RBCC Red Blood Cell Collection

GLMN (FAP48, FAP68, VMGLOM) [Confidence: low (only semi-automatic identification from reviews)]
Glomulin (FK506-binding protein-associated protein; FAP; FKBP-associated protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q92990
ID GLMN_HUMAN Reviewed; 594 AA.
AC Q92990; Q5VVC3; Q9BVE8;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 14-NOV-2003, sequence version 2.
DT 22-JAN-2014, entry version 112.
DE RecName: Full=Glomulin;
DE AltName: Full=FK506-binding protein-associated protein;
DE Short=FAP;
DE AltName: Full=FKBP-associated protein;
GN Name=GLMN; Synonyms=FAP48, FAP68, VMGLOM;
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 2).
RC TISSUE=Leukemia;
RX PubMed=8955134; DOI=10.1074/jbc.271.51.32923;
RA Chambraud B., Radanyi C., Camonis J.H., Shazand K., Rajkowski K.,
RA Baulieu E.-E.;
RT "FAP48, a new protein that forms specific complexes with both
RT immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant
RT drugs FK506 and rapamycin.";
RL J. Biol. Chem. 271:32923-32929(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, PHOSPHORYLATION, AND
RP INTERACTION WITH MET.
RX PubMed=11571281; DOI=10.1074/jbc.M104323200;
RA Grisendi S., Chambraud B., Gout I., Comoglio P.M., Crepaldi T.;
RT "Ligand-regulated binding of FAP68 to the hepatocyte growth factor
RT receptor.";
RL J. Biol. Chem. 276:46632-46638(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANT GVMS
RP ASN-393 DEL.
RX PubMed=11845407; DOI=10.1086/339492;
RA Brouillard P., Boon L.M., Mulliken J.B., Enjolras O., Ghassibe M.,
RA Warman M.L., Tan O.T., Olsen B.R., Vikkula M.;
RT "Mutations in a novel factor, glomulin, are responsible for
RT glomuvenous malformations ('glomangiomas').";
RL Am. J. Hum. Genet. 70:866-874(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [7]
RP FUNCTION.
RX PubMed=12604780; DOI=10.1073/pnas.0438007100;
RA Krummrei U., Baulieu E.-E., Chambraud B.;
RT "The FKBP-associated protein FAP48 is an antiproliferative molecule
RT and a player in T cell activation that increases IL2 synthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:2444-2449(2003).
RN [8]
RP MUTAGENESIS OF PRO-219.
RX PubMed=11164950; DOI=10.1016/S0167-0115(00)00206-8;
RA Neye H.;
RT "Mutation of FKBP associated protein 48 (FAP48) at proline 219
RT disrupts the interaction with FKBP12 and FKBP52.";
RL Regul. Pept. 97:147-152(2001).
RN [9]
RP IDENTIFICATION IN A COMPLEX WITH CUL7; SKP1; FBXW8 AND RBX1.
RX PubMed=12904573; DOI=10.1073/pnas.1733908100;
RA Arai T., Kasper J.S., Skaar J.R., Ali S.H., Takahashi C.,
RA DeCaprio J.A.;
RT "Targeted disruption of p185/Cul7 gene results in abnormal vascular
RT morphogenesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:9855-9860(2003).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
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 [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Essential for normal development of the vasculature. May
CC represent a naturally occurring ligand of the immunophilins FKBP59
CC and FKBP12. May function as an membrane anchoring protein. Isoform
CC 1 may stimulate the p70S6K pathway. Isoform 2 may inhibit cell
CC proliferation and increase IL2 production.
CC -!- SUBUNIT: Monomer. Isoform 1 interacts with notphosphorylated MET
CC and is released upon receptor phosphorylation. Isoform 2 interacts
CC with FKBP59 and FKBP12. Isoform 1 is part of a SCF-like complex
CC consisting of CUL7, RBX1, SKP1, FBXW8 and GLMN isoform 1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=FAP68, FKBP-associated protein 68 kDa;
CC IsoId=Q92990-1; Sequence=Displayed;
CC Name=2; Synonyms=FAP48, FKBP-associated protein 48 kDa;
CC IsoId=Q92990-2; Sequence=VSP_008882, VSP_008883;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- PTM: Phosphorylated on tyrosine residues.
CC -!- DISEASE: Glomuvenous malformations (GVMs) [MIM:138000]:
CC Characterized by the presence of smooth-muscle-like glomus cells
CC in the media surrounding distended vascular lumens. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- MISCELLANEOUS: Rapamycin and FK506 abolish the interaction in a
CC dose dependent manner.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GLMN";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/GLMNID43022ch1p22.html";
CC -----------------------------------------------------------------------
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DR EMBL; U73704; AAC50908.1; -; mRNA.
DR EMBL; AJ347709; CAC69882.1; -; mRNA.
DR EMBL; AJ302735; CAC82938.1; -; mRNA.
DR EMBL; AJ302727; CAC88124.1; -; Genomic_DNA.
DR EMBL; AJ302728; CAC88124.1; JOINED; Genomic_DNA.
DR EMBL; AJ302729; CAC88124.1; JOINED; Genomic_DNA.
DR EMBL; AJ302730; CAC88124.1; JOINED; Genomic_DNA.
DR EMBL; AJ302731; CAC88124.1; JOINED; Genomic_DNA.
DR EMBL; AJ302732; CAC88124.1; JOINED; Genomic_DNA.
DR EMBL; AJ302733; CAC88124.1; JOINED; Genomic_DNA.
DR EMBL; AJ302734; CAC88124.1; JOINED; Genomic_DNA.
DR EMBL; AL451010; CAH70761.1; -; Genomic_DNA.
DR EMBL; CH471097; EAW73098.1; -; Genomic_DNA.
DR EMBL; BC001257; AAH01257.1; -; mRNA.
DR RefSeq; NP_444504.1; NM_053274.2.
DR UniGene; Hs.49105; -.
DR PDB; 4F52; X-ray; 3.00 A; E/F=1-594.
DR PDBsum; 4F52; -.
DR ProteinModelPortal; Q92990; -.
DR SMR; Q92990; 1-583.
DR IntAct; Q92990; 3.
DR MINT; MINT-1407127; -.
DR STRING; 9606.ENSP00000359385; -.
DR PhosphoSite; Q92990; -.
DR DMDM; 38372884; -.
DR PaxDb; Q92990; -.
DR PRIDE; Q92990; -.
DR Ensembl; ENST00000370360; ENSP00000359385; ENSG00000174842.
DR Ensembl; ENST00000495106; ENSP00000436829; ENSG00000174842.
DR GeneID; 11146; -.
DR KEGG; hsa:11146; -.
DR UCSC; uc001dor.3; human.
DR CTD; 11146; -.
DR GeneCards; GC01M092711; -.
DR HGNC; HGNC:14373; GLMN.
DR HPA; HPA031446; -.
DR HPA; HPA031447; -.
DR HPA; HPA031448; -.
DR MIM; 138000; phenotype.
DR MIM; 601749; gene.
DR neXtProt; NX_Q92990; -.
DR Orphanet; 83454; Glomuvenous malformation.
DR PharmGKB; PA134870088; -.
DR eggNOG; NOG149614; -.
DR HOGENOM; HOG000043079; -.
DR HOVERGEN; HBG044811; -.
DR InParanoid; Q92990; -.
DR OMA; KRCQILE; -.
DR OrthoDB; EOG7B05DQ; -.
DR SignaLink; Q92990; -.
DR GeneWiki; GLMN; -.
DR GenomeRNAi; 11146; -.
DR NextBio; 42372; -.
DR PRO; PR:Q92990; -.
DR ArrayExpress; Q92990; -.
DR Bgee; Q92990; -.
DR CleanEx; HS_GLMN; -.
DR Genevestigator; Q92990; -.
DR GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; IPI:MGI.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IPI:MGI.
DR GO; GO:0031464; C:Cul4A-RING ubiquitin ligase complex; IPI:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:MGI.
DR GO; GO:0055105; F:ubiquitin-protein ligase inhibitor activity; IGI:MGI.
DR GO; GO:0042692; P:muscle cell differentiation; IMP:UniProtKB.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IDA:UniProtKB.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0050715; P:positive regulation of cytokine secretion; IMP:UniProtKB.
DR GO; GO:0045086; P:positive regulation of interleukin-2 biosynthetic process; IMP:UniProtKB.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:UniProtKB.
DR GO; GO:0040029; P:regulation of gene expression, epigenetic; IMP:UniProtKB.
DR GO; GO:0032434; P:regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:MGI.
DR GO; GO:0001570; P:vasculogenesis; IMP:UniProtKB.
DR InterPro; IPR019516; Glomulin.
DR InterPro; IPR013877; YAP-bd/Alf4/glomulin.
DR PANTHER; PTHR15430; PTHR15430; 1.
DR Pfam; PF08568; Kinetochor_Ybp2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Coiled coil;
KW Complete proteome; Disease mutation; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 594 Glomulin.
FT /FTId=PRO_0000087513.
FT COILED 188 208 Potential.
FT COILED 272 289 Potential.
FT COMPBIAS 123 126 Poly-Leu.
FT COMPBIAS 273 278 Poly-Glu.
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 406 417 CLLNTSNHSGVE -> EHVTTNGLQDHS (in isoform
FT 2).
FT /FTId=VSP_008882.
FT VAR_SEQ 418 594 Missing (in isoform 2).
FT /FTId=VSP_008883.
FT VARIANT 336 336 L -> S (in dbSNP:rs35258161).
FT /FTId=VAR_061653.
FT VARIANT 393 393 Missing (in GVMs).
FT /FTId=VAR_017241.
FT MUTAGEN 219 219 P->A: Loss of interaction with FKBP12 and
FT FKBP59.
FT HELIX 2 13
FT HELIX 28 37
FT STRAND 38 40
FT HELIX 43 49
FT HELIX 55 60
FT HELIX 62 65
FT HELIX 66 74
FT STRAND 80 82
FT HELIX 84 96
FT HELIX 99 101
FT HELIX 102 106
FT HELIX 107 110
FT HELIX 115 117
FT HELIX 118 135
FT HELIX 140 156
FT HELIX 173 192
FT HELIX 199 222
FT HELIX 236 250
FT STRAND 251 253
FT HELIX 255 257
FT HELIX 283 294
FT TURN 298 302
FT HELIX 309 324
FT HELIX 329 344
FT HELIX 353 357
FT HELIX 359 374
FT HELIX 378 394
FT HELIX 397 411
FT HELIX 414 430
FT TURN 440 442
FT HELIX 444 453
FT TURN 457 461
FT TURN 464 466
FT HELIX 468 484
FT TURN 487 489
FT HELIX 494 496
FT HELIX 498 504
FT HELIX 506 533
FT HELIX 553 555
FT HELIX 556 581
SQ SEQUENCE 594 AA; 68208 MW; CE19050F1F692378 CRC64;
MAVEELQSII KRCQILEEQD FKEEDFGLFQ LAGQRCIEEG HTDQLLEIIQ NEKNKVIIKN
MGWNLVGPVV RCLLCKDKED SKRKVYFLIF DLLVKLCNPK ELLLGLLELI EEPSGKQISQ
SILLLLQPLQ TVIQKLHNKA YSIGLALSTL WNQLSLLPVP YSKEQIQMDD YGLCQCCKAL
IEFTKPFVEE VIDNKENSLE NEKLKDELLK FCFKSLKCPL LTAQFFEQSE EGGNDPFRYF
ASEIIGFLSA IGHPFPKMIF NHGRKKRTWN YLEFEEEENK QLADSMASLA YLVFVQGIHI
DQLPMVLSPL YLLQFNMGHI EVFLQRTEES VISKGLELLE NSLLRIEDNS LLYQYLEIKS
FLTVPQGLVK VMTLCPIETL RKKSLAMLQL YINKLDSQGK YTLFRCLLNT SNHSGVEAFI
IQNIKNQIDM SLKRTRNNKW FTGPQLISLL DLVLFLPEGA ETDLLQNSDR IMASLNLLRY
LVIKDNENDN QTGLWTELGN IENNFLKPLH IGLNMSKAHY EAEIKNSQEA QKSKDLCSIT
VSGEEIPNMP PEMQLKVLHS ALFTFDLIES VLARVEELIE IKTKSTSEEN IGIK
//

MIM 138000
*RECORD*
*FIELD* NO
138000
*FIELD* TI
#138000 GLOMUVENOUS MALFORMATIONS; GVM
;;VENOUS MALFORMATIONS WITH GLOMUS CELLS; VMGLOM;;
read moreGLOMUS TUMORS, MULTIPLE;;
GLOMANGIOMAS, MULTIPLE
*FIELD* TX
A number sign (#) is used with this entry because glomuvenous
malformations can be caused by heterozygous mutation in the glomulin
gene (601749) on chromosome 1p22.

CLINICAL FEATURES

Glomuvenous malformations, also known as 'venous malformations with
glomus cells' or glomangiomas, are similar to mucocutaneous venous
malformations (VMCM; 600195), but clinically are distinguishable: they
have a cobble-stone appearance, they have a consistency harder than that
of venous malformations, and they are painful on palpation (Brouillard
et al., 2002). Histologically, GVMs are distinguishable by the presence
of pathognomonic rounded cells (glomus cells) around the distended
vein-like channels. The term glomus (Latin for ball) stems from the
morphologically similar contractile cells of the Sucquet-Hoyer
arteriovenous anastomoses in glomus bodies that are involved in
cutaneous thermoregulation. Glomus cells in GVMs appear to be
incompletely or improperly differentiated vascular smooth muscle cells,
since they stain positively with smooth muscle cell alpha-actin (102620)
and vimentin (193060). The genetic distinctness of glomuvenous
malformations from mucocutaneous venous malformations is indicated by
the fact that mutations have been found in the TIE2/TEK gene (600221) in
mucocutaneous venous malformations and not in glomuvenous malformations.

Glomus tumors are benign cutaneous neoplasms that are derived from
specialized arteriovenous shunts that occur normally in many parts of
the body. Gorlin et al. (1960) reported 5 affected members in 2
generations of a family. The lesions tend to resemble cavernous
hemangiomas. The distinctive feature is the presence of multiple layers
of glomus cells lining the blood-filled cavities. The tumors are present
at birth or appear in the first 2 decades. Isolated glomus tumor usually
develops later (at about age 33 years on the average), is more
frequently subungual than is the case with multiple tumors, and has no
particular familial occurrence. Reed (1970) presented a pedigree of 4
persons with multiple glomus tumors in 2 generations. Beasley et al.
(1986) reported 4 cases in 3 generations. The 9-year-old proposita had
had 6 soft, blue-black skin lesions from birth, on the forearm, thigh,
and buttocks. All but one were raised.

As pointed out by Boon et al. (1999), glomus tumors, or glomangiomas,
are a clinical and radiologic subtype of venous malformations. Their
pathognomonic characteristic is the presence of undifferentiated smooth
muscle cells (glomus cells) surrounding convoluted venous channels.
Although clinically they look like any venous malformation, they are
more painful on palpation, only partially compressible, and usually not
found in mucosa. In addition, familial aggregation is more common than
in venous malformations generally, and several pedigrees showing
autosomal dominant inheritance have been reported. Iqbal et al. (1998)
estimated that penetrance rises from 70% at age 5 years to 100% by age
30 years.

INHERITANCE

The inheritance of the cutaneous disorder discussed here is
uncomplicated autosomal dominant with many instances of male-to-male
transmission. It is not to be confused with multiple paragangliomata
(168000), which is often referred to as glomus tumors.

MAPPING

Boon et al. (1999) demonstrated that 5 families with inherited cutaneous
venous malformations with glomus cells showed linkage to 1p22-p21 (lod
score = 12.7 at recombination fraction = 0.00). They designated the
locus VMGLOM. Irrthum et al. (2001) reported 7 additional families with
glomangioma showing linkage to 1p22-p21. Combined with the families
reported by Boon et al. (1999), they found a lod score of 18.41 at theta
= 0.0 at marker D1S188. Haplotype analysis revealed evidence for a
founder effect in some of the families. In 4 glomangioma families,
Calvert et al. (2001) found linkage of the trait to 1p22-p21.

Brouillard et al. (2000) reported a physical map based on 18 overlapping
YAC clones spanning the 5-Mb VMGLOM locus. They also reported a
sequence-ready PAC map of 46 clones covering 1.48 Mb within the YAC
contig, a region to which they restricted VMGLOM. They identified
several positional candidate genes within a narrowed region on 1p and
found that one of these, designated originally FAP48 (601749), contained
mutations in cases of GVMs.

MOLECULAR GENETICS

In various autosomal dominant skin disorders, segmental forms reflecting
mosaicism have been reported. Happle (1997) delineated 2 different types
of mosaic manifestation. Type 1 reflects heterozygosity for the
underlying mutation and shows the same degree of severity as that
observed in the corresponding nonmosaic phenotype. In the case of
cutaneous disorders, the skin other than that in the segmental area is
normal. Type 2 originates from loss of heterozygosity and shows an
excessively severe involvement in a segmental area, usually superimposed
on the disseminated lesions of the ordinary trait. Happle and Konig
(1999) surveyed the literature on multiple glomus tumors and found 5
cases suggesting a type 2 segmental involvement. In all of these cases,
a unilateral band-like or patchy arrangement of excessively pronounced
glomus tumors was associated with disseminated lesions corresponding to
the ordinary phenotype, and in 3 cases other family members were
affected with disseminated glomus tumors. The unilateral agminated
(i.e., gathered in clusters) lesions were reported to be present in
early childhood, whereas the disseminated lesions appeared later.

In connection with the demonstration of mutations in glomulin (601749)
as the cause of this disorder, Brouillard et al. (2002) found a somatic
'second hit' mutation in affected tissue of a patient with an inherited
genomic deletion. Furthermore, since all but one of the 14 different
germline mutations identified in patients with GVMs resulted in
premature stop codons, and since the localized nature of the lesions
could be explained by the Knudson 2-hit model, GVMs are likely caused by
complete loss of function of glomulin.

NOMENCLATURE

Strauchen (2002) noted 'a common point of confusion,' namely the
interchangeable use of 'paraganglioma' and 'glomus tumor.' He emphasized
that the glomus tumor is a tumor of modified perivascular smooth muscle,
which frequently presents as a painful subungual mass, and is unrelated
to tumors of the adrenal and extraadrenal paraganglia. Jugulotympanic
paraganglioma is often referred to as a 'glomus jugulare tumor.' This
tumor arises from minute, anatomically dispersed paraganglia located at
the base of the skull and temporal bone and is closely related to
similar tumors of the carotid body and other extraadrenal paraganglia.
It is unrelated to the much more common glomus tumor of skin and soft
tissue.

*FIELD* SA
Chasseuil and Gautard (1961); Kaufman and Clark (1941); Reinhard and
Luders (1970); Rycroft et al. (1975); Sirinavin and Lovrien (1977)
*FIELD* RF
1. Beasley, S. W.; Mel, J.; Chow, C. W.; Jones, P. G.: Hereditary
multiple glomus tumours. Arch. Dis. Child. 61: 801-802, 1986.

2. Boon, L. M.; Brouillard, P.; Irrthum, A.; Karttunen, L.; Warman,
M. L.; Rudolph, R.; Mulliken, J. B.; Olsen, B. R.; Vikkula, M.: A
gene for inherited cutaneous venous anomalies ('glomangiomas') localizes
to chromosome 1p21-22. Am. J. Hum. Genet. 65: 125-133, 1999.

3. Brouillard, P.; Boon, L. M.; Mulliken, J. B.; Enjolras, O.; Ghassibe,
M.; Warman, M. L.; Tan, O. T.; Olsen, B. R.; Vikkula, M.: Mutations
in a novel factor, glomulin, are responsible for glomuvenous malformations
('glomangiomas'). Am. J. Hum. Genet. 70: 866-874, 2002.

4. Brouillard, P.; Olsen, B. R.; Vikkula, M.: High-resolution physical
and transcript map of the locus for venous malformations with glomus
cells (VMGLOM) on chromosome 1p21-p22. Genomics 67: 96-101, 2000.

5. Calvert, J. T.; Burns, S.; Riney, T. J.; Sahoo, T.; Orlow, S. J.;
Nevin, N. C.; Haisley-Royster, C.; Prose, N.; Simpson, S. A.; Speer,
M. C.; Marchuk, D. A.: Additional glomangioma families link to chromosome
1p: no evidence for genetic heterogeneity. Hum. Hered. 51: 180-182,
2001.

6. Chasseuil, R.; Gautard, J.: Tumeurs glomiques familiales: 6 cas
en 4 generations. Bull. Soc. Franc. Derm. Syph. 68: 635-636, 1961.

7. Gorlin, R. J.; Fusaro, R. M.; Benton, J. W.: Multiple glomus tumor
of the pseudocavernous hemangioma type. Arch. Derm. 82: 776-778,
1960.

8. Happle, R.: A rule concerning the segmental manifestation of autosomal
dominant skin disorders: review of clinical examples providing evidence
for dichotomous types of severity. Arch. Derm. 133: 1505-1509, 1997.

9. Happle, R.; Konig, A.: Type 2 segmental manifestation of multiple
glomus tumors: a review and reclassification of 5 case reports. Dermatology 198:
270-272, 1999.

10. Iqbal, A.; Cormack, G. C.; Scerri, G.: Hereditary multiple glomangiomas. Brit.
J. Plast. Surg. 51: 32-37, 1998.

11. Irrthum, A.; Brouillard, P.; Enjolras, O.; Gibbs, N. F.; Eichenfeld,
L. F.; Olsen, B. R.; Mulliken, J. B.; Boon, L. M.; Vikkula, M.: Linkage
disequilibrium narrows locus for venous malformation with glomus cells
(VMGLOM) to a single 1.48 Mbp YAC. Europ. J. Hum. Genet. 9: 34-38,
2001.

12. Kaufman, L. R.; Clark, W. T.: Glomus tumors: report of 4 cases
in same family. Ann. Surg. 114: 1102-1105, 1941.

13. Reed, W. B.: Genetische Aspekte in der Dermatologie. Hautarzt 21:
8-16, 1970.

14. Reinhard, M.; Luders, G.: Zur Pathologie und Klinik multipler
familiaerer Glomustumoren. Arch. Klin. Exp. Derm. 237: 800-810,
1970.

15. Rycroft, R. J. G.; Menter, M. A.; Sharvill, D. E.; Wells, R. S.;
Bannister, L. H.: Hereditary multiple glomus tumours: report of four
families and a review of literature. Trans. St. John's Hosp. Derm.
Soc. 61: 70-81, 1975.

16. Sirinavin, C.; Lovrien, E. W.: Familial multiple glomus tumors.
(Abstract) Birth Defects Orig. Art. Ser. XIII(3B): 255-256, 1977.

17. Strauchen, J. A.: Germ-line mutations in nonsyndromic pheochromocytoma.
(Letter) New Eng. J. Med. 347: 854-855, 2002.

*FIELD* CS

Skin:
Multiple glomus tumors

Lab:
Multiple layers of glomus cells lining blood-filled cavities

Inheritance:
Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 9/30/2002
Victor A. McKusick - updated: 4/12/2002
Michael B. Petersen - updated: 4/17/2001
Victor A. McKusick - updated: 4/11/2001
Victor A. McKusick - updated: 9/25/2000
Victor A. McKusick - updated: 8/5/1999
Victor A. McKusick - updated: 6/25/1999

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

*FIELD* ED
terry: 03/20/2012
mgross: 10/1/2002
carol: 9/30/2002
alopez: 4/15/2002
terry: 4/12/2002
carol: 4/17/2001
terry: 4/11/2001
mcapotos: 10/3/2000
mcapotos: 9/29/2000
terry: 9/25/2000
carol: 4/18/2000
carol: 8/26/1999
jlewis: 8/25/1999
terry: 8/5/1999
carol: 7/9/1999
jlewis: 7/7/1999
terry: 6/25/1999
mimadm: 9/24/1994
carol: 6/28/1993
carol: 12/1/1992
supermim: 3/16/1992
carol: 7/2/1990
supermim: 3/20/1990

MIM 601749
*RECORD*
*FIELD* NO
601749
*FIELD* TI
*601749 GLOMULIN; GLMN
;;FKBP-ASSOCIATED PROTEIN, 48-KD; FAP48;;
FKBP-ASSOCIATED PROTEIN, 68-KD; FAP68
read more*FIELD* TX

CLONING

FK506 and rapamycin are structurally related, potent immunosuppressants
that block intracellular signaling pathways. Their action is mediated in
part by binding to members of the immunophilin protein family, human
members of which include the FK506 binding proteins (FKBPs). Chambraud
et al. (1996) isolated a 48-kD protein that interacts with 2
well-characterized FKBPs, FKBP59 (FKBP4; 600611) and FKBP12 (FKBP1;
186945). The cDNA sequence encodes a protein of 417 amino acids. This
novel protein, named FAP48 for FKBP-associated protein, can interact
with FKBP59 and FKBP12 both in vitro and in vivo; however, binding is
inhibited by FK506 and rapamycin in a dose-dependent manner. FAP48 may
therefore represent a naturally occurring ligand of these
immunosuppressant drug receptors.

The FAP48 gene was described on the basis of an incomplete cDNA
sequence. Brouillard et al. (2002) renamed it 'glomulin' upon finding
that mutations in this gene cause glomuvenous malformations (GVM;
138000). The complete cDNA contains an open reading frame of 1,785
nucleotides encoding a predicted 594-amino acid, 68-kD protein.

GENE FUNCTION

Arai et al. (2003) found that mouse Cul7 (609577) formed a specific SCF
(see CUL1; 603134)-like complex with Skp1 (601434), Fbx29 (FBXW8;
609073), Rbx1 (603814), and Fap68.

GENE STRUCTURE

Brouillard et al. (2002) determined that the glomulin gene consists of
19 exons and extends over 55 kb.

MAPPING

The FAP48 gene was identified within a narrowed region of 1p22-p21
linked to glomuvenous malformations (138000) (Brouillard et al., 2000).

MOLECULAR GENETICS

Brouillard et al. (2002) identified 14 different germline mutations in
patients with glomuvenous malformations. In addition, they found a
somatic 'second hit' mutation in affected tissue of a patient with an
inherited genomic deletion. Since all but one of the mutations resulted
in premature stop codons, and since the localized nature of the lesions
could be explained by the Knudson 2-hit model, glomuvenous malformations
are likely caused by complete loss of function of glomulin. The abnormal
phenotype of vascular smooth-muscle cells in GVMs suggested that
glomulin plays an important role in differentiation of these cells--and,
thereby, in vascular morphogenesis--especially in cutaneous veins.

*FIELD* AV
.0001
GLOMUVENOUS MALFORMATIONS
GLMN, 8.4-KB DEL, 2-BP GG INS

In a family in which 2 brothers and 2 daughters of 1 of them had
glomuvenous malformations (138000), Brouillard et al. (2002) found an
8.4-kb deletion beginning in intron 7 and ending in intron 13 of the
GLMN gene. There was an addition, an insertion of GG. In tumors they
identified a second hit (mutation on the other allele), a deletion of
CAGAA beginning with nucleotide 980.

.0002
GLOMUVENOUS MALFORMATIONS
GLMN, 5-BP DEL, 980CAGAA

See Brouillard et al. (2002) and 601749.0001.

.0003
GLOMUVENOUS MALFORMATIONS
GLMN, 5-BP DEL, 157AAGAA

In 7 presumably unrelated families with glomuvenous malformations
(138000) in which Irrthum et al. (2001) had found strong evidence for
linkage disequilibrium, Brouillard et al. (2002) found the same 5-bp
deletion in the GLMN gene causing a frameshift and premature stop. Thus
the common ancestral origin of the haplotype was established.

.0004
GLOMUVENOUS MALFORMATIONS
GLMN, ASN394 DEL

Only 1 of the 14 different germline mutations in the GLMN gene
identified by Brouillard et al. (2002) in patients with GVMs (138000)
did not cause a premature stop codon: a deletion of 3 nucleotides
(1179delCAA), equivalent to the removal of an asparagine at position
394.

*FIELD* RF
1. Arai, T.; Kasper, J. S.; Skaar, J. R.; Ali, S. H.; Takahashi, C.;
DeCaprio, J. A.: Targeted disruption of p185/Cul7 gene results in
abnormal vascular morphogenesis. Proc. Nat. Acad. Sci. 100: 9855-9860,
2003.

2. Brouillard, P.; Boon, L. M.; Mulliken, J. B.; Enjolras, O.; Ghassibe,
M.; Warman, M. L.; Tan, O. T.; Olsen, B. R.; Vikkula, M.: Mutations
in a novel factor, glomulin, are responsible for glomuvenous malformations
('glomangiomas'). Am. J. Hum. Genet. 70: 866-874, 2002.

3. Brouillard, P.; Olsen, B. R.; Vikkula, M.: High-resolution physical
and transcript map of the locus for venous malformations with glomus
cells (VMGLOM) on chromosome 1p21-p22. Genomics 67: 96-101, 2000.

4. Chambraud, B.; Radanyi, C.; Camonis, J. H.; Shazand, K.; Rajkowski,
K.; Baulieu, E.-E.: FAP48, a new protein that forms specific complexes
with both immunophilins FKBP59 and FKBP12. J. Biol. Chem. 271: 32923-32929,
1996.

5. Irrthum, A.; Brouillard, P.; Enjolras, O.; Gibbs, N. F.; Eichenfeld,
L. F.; Olsen, B. R.; Mulliken, J. B.; Boon, L. M.; Vikkula, M.: Linkage
disequilibrium narrows locus for venous malformation with glomus cells
(VMGLOM) to a single 1.48 Mbp YAC. Europ. J. Hum. Genet. 9: 34-38,
2001.

*FIELD* CN
Patricia A. Hartz - updated: 09/13/2005
Victor A. McKusick - updated: 4/12/2002

*FIELD* CD
Jennifer P. Macke: 4/11/1997

*FIELD* ED
mgross: 09/13/2005
mgross: 9/13/2005
alopez: 4/15/2002
terry: 4/12/2002
carol: 7/27/1999
terry: 7/12/1999
alopez: 5/5/1997
alopez: 4/14/1997