Full text data of SF3B4
SF3B4
(SAP49)
[Confidence: low (only semi-automatic identification from reviews)]
Splicing factor 3B subunit 4 (Pre-mRNA-splicing factor SF3b 49 kDa subunit; SF3b50; Spliceosome-associated protein 49; SAP 49)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Splicing factor 3B subunit 4 (Pre-mRNA-splicing factor SF3b 49 kDa subunit; SF3b50; Spliceosome-associated protein 49; SAP 49)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q15427
ID SF3B4_HUMAN Reviewed; 424 AA.
AC Q15427; Q5SZ63;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Splicing factor 3B subunit 4;
DE AltName: Full=Pre-mRNA-splicing factor SF3b 49 kDa subunit;
DE AltName: Full=SF3b50;
DE AltName: Full=Spliceosome-associated protein 49;
DE Short=SAP 49;
GN Name=SF3B4; Synonyms=SAP49;
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 [GENOMIC DNA].
RX PubMed=7958871;
RA Champion-Arnaud P., Reed R.;
RT "The prespliceosome components SAP 49 and SAP 145 interact in a
RT complex implicated in tethering U2 snRNP to the branch site.";
RL Genes Dev. 8:1974-1983(1994).
RN [2]
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 [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin, and Testis;
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 [5]
RP PROTEIN SEQUENCE OF 2-23, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Ovarian carcinoma;
RA Bienvenut W.V., Lilla S., von Kriegsheim A., Lempens A., Kolch W.;
RL Submitted (DEC-2008) to UniProtKB.
RN [6]
RP CHARACTERIZATION OF THE SPLICEOSOME.
RX PubMed=10882114; DOI=10.1016/S1097-2765(00)80318-4;
RA Das R., Zhou Z., Reed R.;
RT "Functional association of U2 snRNP with the ATP-independent
RT spliceosomal complex E.";
RL Mol. Cell 5:779-787(2000).
RN [7]
RP IDENTIFICATION IN THE SF3B COMPLEX.
RX PubMed=12234937; DOI=10.1093/emboj/cdf480;
RA Will C.L., Urlaub H., Achsel T., Gentzel M., Wilm M., Luehrmann R.;
RT "Characterization of novel SF3b and 17S U2 snRNP proteins, including a
RT human Prp5p homologue and an SF3b DEAD-box protein.";
RL EMBO J. 21:4978-4988(2002).
RN [8]
RP IDENTIFICATION IN THE SF3B COMPLEX, AND ELECTRON MICROSCOPY OF THE
RP SF3B COMPLEX.
RX PubMed=12738865; DOI=10.1126/science.1084155;
RA Golas M.M., Sander B., Will C.L., Luhrmann R., Stark H.;
RT "Molecular architecture of the multiprotein splicing factor SF3b.";
RL Science 300:980-984(2003).
RN [9]
RP IDENTIFICATION IN A COMPLEX WITH THE U11/U12 SPLICEOSOME, AND MASS
RP SPECTROMETRY.
RX PubMed=15146077; DOI=10.1261/rna.7320604;
RA Will C.L., Schneider C., Hossbach M., Urlaub H., Rauhut R.,
RA Elbashir S., Tuschl T., Luehrmann R.;
RT "The human 18S U11/U12 snRNP contains a set of novel proteins not
RT found in the U2-dependent spliceosome.";
RL RNA 10:929-941(2004).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-56, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
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 [12]
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 [13]
RP INVOLVEMENT IN AFD1.
RX PubMed=22541558; DOI=10.1016/j.ajhg.2012.04.004;
RA Bernier F.P., Caluseriu O., Ng S., Schwartzentruber J.,
RA Buckingham K.J., Innes A.M., Jabs E.W., Innis J.W., Schuette J.L.,
RA Gorski J.L., Byers P.H., Andelfinger G., Siu V., Lauzon J.,
RA Fernandez B.A., McMillin M., Scott R.H., Racher H., Majewski J.,
RA Nickerson D.A., Shendure J., Bamshad M.J., Parboosingh J.S.;
RT "Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal
RT complex, causes Nager syndrome.";
RL Am. J. Hum. Genet. 90:925-933(2012).
RN [14]
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).
RN [15]
RP STRUCTURE BY NMR OF 4-184.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of RRM domains in splicing factor 3B.";
RL Submitted (NOV-2005) to the PDB data bank.
CC -!- FUNCTION: Subunit of the splicing factor SF3B required for 'A'
CC complex assembly formed by the stable binding of U2 snRNP to the
CC branchpoint sequence (BPS) in pre-mRNA. Sequence independent
CC binding of SF3A/SF3B complex upstream of the branch site is
CC essential, it may anchor U2 snRNP to the pre-mRNA. May also be
CC involved in the assembly of the 'E' complex. SF3B4 has been found
CC in complex 'B' and 'C' as well. Belongs also to the minor U12-
CC dependent spliceosome, which is involved in the splicing of rare
CC class of nuclear pre-mRNA intron.
CC -!- SUBUNIT: Component of splicing factor SF3B which is composed of at
CC least eight subunits; SF3B1/SAP155/SF3B155, SF3B2/SAP145/SF3B145,
CC SF3B3/SAP130/SF3B130, SF3B4/SAP49/SF3B49, SF3B14A, PHF5A/SF3B14B,
CC SF3B10 and SF3B125. SF3B associates with the splicing factor SF3A
CC and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins
CC complex (U2 snRNP). Component of the U11/U12 snRNPs that are part
CC of the U12-type spliceosome. SF3B4 interacts directly with SF3B2.
CC -!- INTERACTION:
CC O75934:BCAS2; NbExp=2; IntAct=EBI-348469, EBI-1050106;
CC Q15029:EFTUD2; NbExp=2; IntAct=EBI-348469, EBI-357897;
CC P62993:GRB2; NbExp=2; IntAct=EBI-348469, EBI-401755;
CC Q6P2Q9:PRPF8; NbExp=2; IntAct=EBI-348469, EBI-538479;
CC P98175:RBM10; NbExp=2; IntAct=EBI-348469, EBI-721525;
CC Q13435:SF3B2; NbExp=3; IntAct=EBI-348469, EBI-749111;
CC Q9BRX9:WDR83; NbExp=2; IntAct=EBI-348469, EBI-7705033;
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity).
CC -!- DISEASE: Acrofacial dysostosis 1, Nager type (AFD1) [MIM:154400]:
CC A form of acrofacial dysostosis, a group of disorders which are
CC characterized by malformation of the craniofacial skeleton and the
CC limbs. The major facial features of AFD1 include downslanted
CC palpebral fissures, midface retrusion, and micrognathia, the
CC latter of which often requires the placement of a tracheostomy in
CC early childhood. Limb defects typically involve the anterior
CC (radial) elements of the upper limbs and manifest as small or
CC absent thumbs, triphalangeal thumbs, radial hyoplasia or aplasia,
CC and radioulnar synostosis. Phocomelia of the upper limbs and,
CC occasionally, lower-limb defects have also been reported. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the SF3B4 family.
CC -!- SIMILARITY: Contains 2 RRM (RNA recognition motif) domains.
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DR EMBL; L35013; AAA60300.1; -; Genomic_DNA.
DR EMBL; AL591493; CAI12554.1; -; Genomic_DNA.
DR EMBL; AL590487; CAI12554.1; JOINED; Genomic_DNA.
DR EMBL; AL590487; CAI12648.1; -; Genomic_DNA.
DR EMBL; AL591493; CAI12648.1; JOINED; Genomic_DNA.
DR EMBL; CH471121; EAW53595.1; -; Genomic_DNA.
DR EMBL; BC004273; AAH04273.1; -; mRNA.
DR EMBL; BC013886; AAH13886.1; -; mRNA.
DR EMBL; BC090883; AAH90883.1; -; mRNA.
DR PIR; A54964; A54964.
DR RefSeq; NP_005841.1; NM_005850.4.
DR RefSeq; XP_005244883.1; XM_005244826.1.
DR RefSeq; XP_005277388.1; XM_005277331.1.
DR UniGene; Hs.516160; -.
DR PDB; 1X5T; NMR; -; A=102-184.
DR PDB; 1X5U; NMR; -; A=5-96.
DR PDBsum; 1X5T; -.
DR PDBsum; 1X5U; -.
DR ProteinModelPortal; Q15427; -.
DR SMR; Q15427; 5-186.
DR IntAct; Q15427; 36.
DR MINT; MINT-1032702; -.
DR STRING; 9606.ENSP00000271628; -.
DR PhosphoSite; Q15427; -.
DR DMDM; 2500587; -.
DR PaxDb; Q15427; -.
DR PeptideAtlas; Q15427; -.
DR PRIDE; Q15427; -.
DR DNASU; 10262; -.
DR Ensembl; ENST00000271628; ENSP00000271628; ENSG00000143368.
DR Ensembl; ENST00000582851; ENSP00000462063; ENSG00000263977.
DR GeneID; 10262; -.
DR KEGG; hsa:10262; -.
DR UCSC; uc001etk.2; human.
DR CTD; 10262; -.
DR GeneCards; GC01M149895; -.
DR HGNC; HGNC:10771; SF3B4.
DR HPA; HPA028578; -.
DR MIM; 154400; phenotype.
DR MIM; 605593; gene.
DR neXtProt; NX_Q15427; -.
DR Orphanet; 245; Nager syndrome.
DR PharmGKB; PA35689; -.
DR eggNOG; COG0724; -.
DR HOGENOM; HOG000200535; -.
DR HOVERGEN; HBG002295; -.
DR InParanoid; Q15427; -.
DR KO; K12831; -.
DR OMA; HKGERHG; -.
DR PhylomeDB; Q15427; -.
DR Reactome; REACT_1675; mRNA Processing.
DR Reactome; REACT_71; Gene Expression.
DR EvolutionaryTrace; Q15427; -.
DR GeneWiki; SF3B4; -.
DR GenomeRNAi; 10262; -.
DR NextBio; 38880; -.
DR PRO; PR:Q15427; -.
DR ArrayExpress; Q15427; -.
DR Bgee; Q15427; -.
DR CleanEx; HS_SF3B4; -.
DR Genevestigator; Q15427; -.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005689; C:U12-type spliceosomal complex; IDA:UniProtKB.
DR GO; GO:0000166; F:nucleotide binding; IEA:InterPro.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0000398; P:mRNA splicing, via spliceosome; IC:HGNC.
DR Gene3D; 3.30.70.330; -; 2.
DR InterPro; IPR012677; Nucleotide-bd_a/b_plait.
DR InterPro; IPR000504; RRM_dom.
DR Pfam; PF00076; RRM_1; 2.
DR SMART; SM00360; RRM; 2.
DR PROSITE; PS50102; RRM; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; mRNA processing; mRNA splicing; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat; RNA-binding; Spliceosome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 424 Splicing factor 3B subunit 4.
FT /FTId=PRO_0000081955.
FT DOMAIN 13 91 RRM 1.
FT DOMAIN 100 179 RRM 2.
FT COMPBIAS 215 218 Poly-Pro.
FT COMPBIAS 262 268 Poly-Pro.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 56 56 Phosphotyrosine.
FT TURN 11 13
FT STRAND 14 18
FT HELIX 26 34
FT STRAND 39 43
FT STRAND 48 50
FT STRAND 57 63
FT HELIX 64 73
FT STRAND 74 76
FT STRAND 85 88
FT TURN 89 92
FT STRAND 102 105
FT HELIX 113 121
FT STRAND 126 128
FT TURN 136 138
FT STRAND 143 151
FT HELIX 152 160
FT TURN 161 164
FT STRAND 173 177
SQ SEQUENCE 424 AA; 44386 MW; 212472A25D3FF002 CRC64;
MAAGPISERN QDATVYVGGL DEKVSEPLLW ELFLQAGPVV NTHMPKDRVT GQHQGYGFVE
FLSEEDADYA IKIMNMIKLY GKPIRVNKAS AHNKNLDVGA NIFIGNLDPE IDEKLLYDTF
SAFGVILQTP KIMRDPDTGN SKGYAFINFA SFDASDAAIE AMNGQYLCNR PITVSYAFKK
DSKGERHGSA AERLLAAQNP LSQADRPHQL FADAPPPPSA PNPVVSSLGS GLPPPGMPPP
GSFPPPVPPP GALPPGIPPA MPPPPMPPGA AGHGPPSAGT PGAGHPGHGH SHPHPFPPGG
MPHPGMSQMQ LAHHGPHGLG HPHAGPPGSG GQPPPRPPPG MPHPGPPPMG MPPRGPPFGS
PMGHPGPMPP HGMRGPPPLM PPHGYTGPPR PPPYGYQRGP LPPPRPTPRP PVPPRGPLRG
PLPQ
//
ID SF3B4_HUMAN Reviewed; 424 AA.
AC Q15427; Q5SZ63;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Splicing factor 3B subunit 4;
DE AltName: Full=Pre-mRNA-splicing factor SF3b 49 kDa subunit;
DE AltName: Full=SF3b50;
DE AltName: Full=Spliceosome-associated protein 49;
DE Short=SAP 49;
GN Name=SF3B4; Synonyms=SAP49;
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 [GENOMIC DNA].
RX PubMed=7958871;
RA Champion-Arnaud P., Reed R.;
RT "The prespliceosome components SAP 49 and SAP 145 interact in a
RT complex implicated in tethering U2 snRNP to the branch site.";
RL Genes Dev. 8:1974-1983(1994).
RN [2]
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 [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin, and Testis;
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 [5]
RP PROTEIN SEQUENCE OF 2-23, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Ovarian carcinoma;
RA Bienvenut W.V., Lilla S., von Kriegsheim A., Lempens A., Kolch W.;
RL Submitted (DEC-2008) to UniProtKB.
RN [6]
RP CHARACTERIZATION OF THE SPLICEOSOME.
RX PubMed=10882114; DOI=10.1016/S1097-2765(00)80318-4;
RA Das R., Zhou Z., Reed R.;
RT "Functional association of U2 snRNP with the ATP-independent
RT spliceosomal complex E.";
RL Mol. Cell 5:779-787(2000).
RN [7]
RP IDENTIFICATION IN THE SF3B COMPLEX.
RX PubMed=12234937; DOI=10.1093/emboj/cdf480;
RA Will C.L., Urlaub H., Achsel T., Gentzel M., Wilm M., Luehrmann R.;
RT "Characterization of novel SF3b and 17S U2 snRNP proteins, including a
RT human Prp5p homologue and an SF3b DEAD-box protein.";
RL EMBO J. 21:4978-4988(2002).
RN [8]
RP IDENTIFICATION IN THE SF3B COMPLEX, AND ELECTRON MICROSCOPY OF THE
RP SF3B COMPLEX.
RX PubMed=12738865; DOI=10.1126/science.1084155;
RA Golas M.M., Sander B., Will C.L., Luhrmann R., Stark H.;
RT "Molecular architecture of the multiprotein splicing factor SF3b.";
RL Science 300:980-984(2003).
RN [9]
RP IDENTIFICATION IN A COMPLEX WITH THE U11/U12 SPLICEOSOME, AND MASS
RP SPECTROMETRY.
RX PubMed=15146077; DOI=10.1261/rna.7320604;
RA Will C.L., Schneider C., Hossbach M., Urlaub H., Rauhut R.,
RA Elbashir S., Tuschl T., Luehrmann R.;
RT "The human 18S U11/U12 snRNP contains a set of novel proteins not
RT found in the U2-dependent spliceosome.";
RL RNA 10:929-941(2004).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-56, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
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 [12]
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 [13]
RP INVOLVEMENT IN AFD1.
RX PubMed=22541558; DOI=10.1016/j.ajhg.2012.04.004;
RA Bernier F.P., Caluseriu O., Ng S., Schwartzentruber J.,
RA Buckingham K.J., Innes A.M., Jabs E.W., Innis J.W., Schuette J.L.,
RA Gorski J.L., Byers P.H., Andelfinger G., Siu V., Lauzon J.,
RA Fernandez B.A., McMillin M., Scott R.H., Racher H., Majewski J.,
RA Nickerson D.A., Shendure J., Bamshad M.J., Parboosingh J.S.;
RT "Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal
RT complex, causes Nager syndrome.";
RL Am. J. Hum. Genet. 90:925-933(2012).
RN [14]
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).
RN [15]
RP STRUCTURE BY NMR OF 4-184.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of RRM domains in splicing factor 3B.";
RL Submitted (NOV-2005) to the PDB data bank.
CC -!- FUNCTION: Subunit of the splicing factor SF3B required for 'A'
CC complex assembly formed by the stable binding of U2 snRNP to the
CC branchpoint sequence (BPS) in pre-mRNA. Sequence independent
CC binding of SF3A/SF3B complex upstream of the branch site is
CC essential, it may anchor U2 snRNP to the pre-mRNA. May also be
CC involved in the assembly of the 'E' complex. SF3B4 has been found
CC in complex 'B' and 'C' as well. Belongs also to the minor U12-
CC dependent spliceosome, which is involved in the splicing of rare
CC class of nuclear pre-mRNA intron.
CC -!- SUBUNIT: Component of splicing factor SF3B which is composed of at
CC least eight subunits; SF3B1/SAP155/SF3B155, SF3B2/SAP145/SF3B145,
CC SF3B3/SAP130/SF3B130, SF3B4/SAP49/SF3B49, SF3B14A, PHF5A/SF3B14B,
CC SF3B10 and SF3B125. SF3B associates with the splicing factor SF3A
CC and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins
CC complex (U2 snRNP). Component of the U11/U12 snRNPs that are part
CC of the U12-type spliceosome. SF3B4 interacts directly with SF3B2.
CC -!- INTERACTION:
CC O75934:BCAS2; NbExp=2; IntAct=EBI-348469, EBI-1050106;
CC Q15029:EFTUD2; NbExp=2; IntAct=EBI-348469, EBI-357897;
CC P62993:GRB2; NbExp=2; IntAct=EBI-348469, EBI-401755;
CC Q6P2Q9:PRPF8; NbExp=2; IntAct=EBI-348469, EBI-538479;
CC P98175:RBM10; NbExp=2; IntAct=EBI-348469, EBI-721525;
CC Q13435:SF3B2; NbExp=3; IntAct=EBI-348469, EBI-749111;
CC Q9BRX9:WDR83; NbExp=2; IntAct=EBI-348469, EBI-7705033;
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity).
CC -!- DISEASE: Acrofacial dysostosis 1, Nager type (AFD1) [MIM:154400]:
CC A form of acrofacial dysostosis, a group of disorders which are
CC characterized by malformation of the craniofacial skeleton and the
CC limbs. The major facial features of AFD1 include downslanted
CC palpebral fissures, midface retrusion, and micrognathia, the
CC latter of which often requires the placement of a tracheostomy in
CC early childhood. Limb defects typically involve the anterior
CC (radial) elements of the upper limbs and manifest as small or
CC absent thumbs, triphalangeal thumbs, radial hyoplasia or aplasia,
CC and radioulnar synostosis. Phocomelia of the upper limbs and,
CC occasionally, lower-limb defects have also been reported. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the SF3B4 family.
CC -!- SIMILARITY: Contains 2 RRM (RNA recognition motif) domains.
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; L35013; AAA60300.1; -; Genomic_DNA.
DR EMBL; AL591493; CAI12554.1; -; Genomic_DNA.
DR EMBL; AL590487; CAI12554.1; JOINED; Genomic_DNA.
DR EMBL; AL590487; CAI12648.1; -; Genomic_DNA.
DR EMBL; AL591493; CAI12648.1; JOINED; Genomic_DNA.
DR EMBL; CH471121; EAW53595.1; -; Genomic_DNA.
DR EMBL; BC004273; AAH04273.1; -; mRNA.
DR EMBL; BC013886; AAH13886.1; -; mRNA.
DR EMBL; BC090883; AAH90883.1; -; mRNA.
DR PIR; A54964; A54964.
DR RefSeq; NP_005841.1; NM_005850.4.
DR RefSeq; XP_005244883.1; XM_005244826.1.
DR RefSeq; XP_005277388.1; XM_005277331.1.
DR UniGene; Hs.516160; -.
DR PDB; 1X5T; NMR; -; A=102-184.
DR PDB; 1X5U; NMR; -; A=5-96.
DR PDBsum; 1X5T; -.
DR PDBsum; 1X5U; -.
DR ProteinModelPortal; Q15427; -.
DR SMR; Q15427; 5-186.
DR IntAct; Q15427; 36.
DR MINT; MINT-1032702; -.
DR STRING; 9606.ENSP00000271628; -.
DR PhosphoSite; Q15427; -.
DR DMDM; 2500587; -.
DR PaxDb; Q15427; -.
DR PeptideAtlas; Q15427; -.
DR PRIDE; Q15427; -.
DR DNASU; 10262; -.
DR Ensembl; ENST00000271628; ENSP00000271628; ENSG00000143368.
DR Ensembl; ENST00000582851; ENSP00000462063; ENSG00000263977.
DR GeneID; 10262; -.
DR KEGG; hsa:10262; -.
DR UCSC; uc001etk.2; human.
DR CTD; 10262; -.
DR GeneCards; GC01M149895; -.
DR HGNC; HGNC:10771; SF3B4.
DR HPA; HPA028578; -.
DR MIM; 154400; phenotype.
DR MIM; 605593; gene.
DR neXtProt; NX_Q15427; -.
DR Orphanet; 245; Nager syndrome.
DR PharmGKB; PA35689; -.
DR eggNOG; COG0724; -.
DR HOGENOM; HOG000200535; -.
DR HOVERGEN; HBG002295; -.
DR InParanoid; Q15427; -.
DR KO; K12831; -.
DR OMA; HKGERHG; -.
DR PhylomeDB; Q15427; -.
DR Reactome; REACT_1675; mRNA Processing.
DR Reactome; REACT_71; Gene Expression.
DR EvolutionaryTrace; Q15427; -.
DR GeneWiki; SF3B4; -.
DR GenomeRNAi; 10262; -.
DR NextBio; 38880; -.
DR PRO; PR:Q15427; -.
DR ArrayExpress; Q15427; -.
DR Bgee; Q15427; -.
DR CleanEx; HS_SF3B4; -.
DR Genevestigator; Q15427; -.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005689; C:U12-type spliceosomal complex; IDA:UniProtKB.
DR GO; GO:0000166; F:nucleotide binding; IEA:InterPro.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0000398; P:mRNA splicing, via spliceosome; IC:HGNC.
DR Gene3D; 3.30.70.330; -; 2.
DR InterPro; IPR012677; Nucleotide-bd_a/b_plait.
DR InterPro; IPR000504; RRM_dom.
DR Pfam; PF00076; RRM_1; 2.
DR SMART; SM00360; RRM; 2.
DR PROSITE; PS50102; RRM; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; mRNA processing; mRNA splicing; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat; RNA-binding; Spliceosome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 424 Splicing factor 3B subunit 4.
FT /FTId=PRO_0000081955.
FT DOMAIN 13 91 RRM 1.
FT DOMAIN 100 179 RRM 2.
FT COMPBIAS 215 218 Poly-Pro.
FT COMPBIAS 262 268 Poly-Pro.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 56 56 Phosphotyrosine.
FT TURN 11 13
FT STRAND 14 18
FT HELIX 26 34
FT STRAND 39 43
FT STRAND 48 50
FT STRAND 57 63
FT HELIX 64 73
FT STRAND 74 76
FT STRAND 85 88
FT TURN 89 92
FT STRAND 102 105
FT HELIX 113 121
FT STRAND 126 128
FT TURN 136 138
FT STRAND 143 151
FT HELIX 152 160
FT TURN 161 164
FT STRAND 173 177
SQ SEQUENCE 424 AA; 44386 MW; 212472A25D3FF002 CRC64;
MAAGPISERN QDATVYVGGL DEKVSEPLLW ELFLQAGPVV NTHMPKDRVT GQHQGYGFVE
FLSEEDADYA IKIMNMIKLY GKPIRVNKAS AHNKNLDVGA NIFIGNLDPE IDEKLLYDTF
SAFGVILQTP KIMRDPDTGN SKGYAFINFA SFDASDAAIE AMNGQYLCNR PITVSYAFKK
DSKGERHGSA AERLLAAQNP LSQADRPHQL FADAPPPPSA PNPVVSSLGS GLPPPGMPPP
GSFPPPVPPP GALPPGIPPA MPPPPMPPGA AGHGPPSAGT PGAGHPGHGH SHPHPFPPGG
MPHPGMSQMQ LAHHGPHGLG HPHAGPPGSG GQPPPRPPPG MPHPGPPPMG MPPRGPPFGS
PMGHPGPMPP HGMRGPPPLM PPHGYTGPPR PPPYGYQRGP LPPPRPTPRP PVPPRGPLRG
PLPQ
//
MIM
154400
*RECORD*
*FIELD* NO
154400
*FIELD* TI
#154400 ACROFACIAL DYSOSTOSIS 1, NAGER TYPE; AFD1
;;MANDIBULOFACIAL DYSOSTOSIS, TREACHER COLLINS TYPE, WITH LIMB ANOMALIES;;
read moreNAGER ACROFACIAL DYSOSTOSIS;;
AFD, NAGER TYPE;;
NAGER SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
Nager type of acrofacial dysostosis (AFD1) is caused by heterozygous
mutation in the SF3B4 gene (605593) on chromosome 1q12-q21.
DESCRIPTION
Nager syndrome is the prototype for a group of disorders collectively
referred to as the acrofacial dysostoses (AFDs), which are characterized
by malformation of the craniofacial skeleton and the limbs. The major
facial features of Nager syndrome include downslanted palpebral
fissures, midface retrusion, and micrognathia, the latter of which often
requires the placement of a tracheostomy in early childhood. Limb
defects typically involve the anterior (radial) elements of the upper
limbs and manifest as small or absent thumbs, triphalangeal thumbs,
radial hyoplasia or aplasia, and radioulnar synostosis. Phocomelia of
the upper limbs and, occasionally, lower-limb defects have also been
reported. The presence of anterior upper-limb defects and the typical
lack of lower-limb involvement distinguishes Nager syndrome from Miller
syndrome (263750), another rare AFD; however, distingushing Nager
syndrome from other AFDs, including Miller syndrome, can be challenging
(summary by Bernier et al., 2012).
CLINICAL FEATURES
Nager acrofacial dysostosis was recognized as a specific entity by Nager
and de Reynier (1948), but was probably first reported by Slingenberg
(1908). The limb deformities in the Nager syndrome consist of absence of
radius, radioulnar synostosis, and hypoplasia or absence of the thumbs.
The mandibulofacial dysostosis is characterized mainly by severe
micrognathia and malar hypoplasia.
The disorder reported by Walker (1974) in sibs whose parents were normal
may have been Nager syndrome.
Weinbaum et al. (1981) described a kindred in which the proband had
classic Nager syndrome and 5 other persons covering 4 generations showed
lesser expression. They suggested that ptosis of the lower lids,
hypoplasia of the lower lid eyelashes, and cartilaginous pegs between
the antitragus and lobule are minimal expressions of the syndrome.
Richieri-Costa et al. (1983) described 2 sisters, offspring of
nonconsanguineous parents, who had facial and skeletal anomalies. One
had mandibulofacial dysostosis with bilateral radial ray anomalies. The
other had cleft lip and palate with hypoplastic thumbs.
Halal et al. (1983) reported 4 patients and reviewed all previous cases.
This led to an extended characterization of Nager acrofacial dysostosis,
e.g., description of lower limb defects. The differentiation from AFD
with postaxial defects (263750), the hemifacial microsomia/Goldenhar
radial defect syndrome, and other syndromes was discussed.
Opitz (1987) suggested that Nager acrofacial dysostosis represents an
'anomaly' rather than a syndrome because of its apparent causal
heterogeneity.
Aylsworth et al. (1987) described findings in a father and child
consistent with the Nager syndrome and supporting autosomal dominant
inheritance. In addition to cranial features, the child had a small left
thumb and absence of the right thumb. The father had similar facial
features, a nonfunctional, proximally placed right thumb, and the
history of a rudimentary left thumb that was removed during childhood.
Aylsworth and Lin (1990) described an affected father and 2 sons. One of
the sons had Hirschsprung disease.
Goldstein and Mirkin (1988) described an unusually severe form.
Palomeque et al. (1990) also reported a severely affected patient.
Bonthron et al. (1993) reported the case of a girl with Nager acrofacial
dysostosis who had a maternal aunt and maternal great-grandfather with a
short distal phalanx of the thumb (type D brachydactyly) and a maternal
grandmother with a bilateral congenital anomaly of the thumbnails
referred to as dystrophia unguis mediana canaliformis (Seller, 1974).
The thumb in this case was longitudinally divided. The family was
presented as supporting dominant inheritance.
Fryns et al. (1996) reported an adult male who, in addition to typical
manifestations, had agenesis of the corpus callosum, strabismus,
equinovarus position of both feet, cryptorchidism, and blind-ending
fistula in the middle of the anoscrotal raphe. The patient died at the
age of 50 years from heart failure due to a complete atrioventricular
block.
McDonald and Gorski (1993) presented a summary of 76 previously reported
cases and added 2 new cases. Proximal radioulnar synostosis was found in
16 of 19 cases in whom appropriate studies were performed.
See 263750 for the Miller acrofacial syndrome in which postaxial limb
changes (rather than preaxial as in Nager syndrome) are associated with
facial dysostosis.
See split-hand deformity with mandibulofacial dysostosis (183700).
INHERITANCE
There is evidence of autosomal dominant and autosomal recessive
inheritance of Nager acrofacial dysostosis.
Marden et al. (1964) described an infant with this syndrome whose father
and mother were 42 and 41 years of age, respectively, at the time of his
birth, thus suggesting dominant mutation.
Lowry (1977) described the anomaly in a patient whose father and mother
were 44 and 38 years of age, respectively, at her birth, compatible with
new dominant mutation.
Burton and Nadler (1977) described a case in the offspring of first
cousins; the father was aged 37 years.
Aylsworth et al. (1987) described a family with affected father and
child and Aylsworth and Lin (1990) described a family with affected
father and 2 sons, supporting the notion that some cases are caused by
autosomal dominant mutations (Aylsworth et al., 1991).
Chemke et al. (1988) reported affected male and female sibs; the parents
were unrelated.
Byrd et al. (1988) described 4 patients with Nager acrofacial
dysostosis, including a pair of concordantly affected monozygotic twins.
McDonald and Gorski (1993) presented a summary of 76 previously reported
cases and added 2 new cases. They favored inheritance as a pleiotropic
disorder with markedly variable penetrance and expressivity, but granted
that the occurrence of affected sibs with normal parents suggested
genetic heterogeneity with the existence of an autosomal recessive form.
They found 5 families with normal parents and 2 affected sibs.
DIAGNOSIS
- Prenatal Diagnosis
Hecht et al. (1987) identified the Nager syndrome in a newborn infant
and in a subsequent sib by prenatal ultrasonography. They presented this
as evidence of autosomal recessive inheritance.
CYTOGENETICS
Waggoner et al. (1999) reported a case of Nager syndrome with deletion
of the heterochromatic block and adjacent euchromatin of chromosome 1q
([46,XY,del(1)(q12q21.1)] or [46,XY,del(1)q12q21.3]). The affected child
also had severe aortic stenosis and right pulmonary bronchial stenosis.
The authors suggested that the deleted 1q region may contain genes
crucial for normal limb, craniofacial, and/or cardiopulmonary
development.
- Genetic Heterogeneity of Nager Syndrome
Zori et al. (1993) suggested that the gene for this disorder may reside
on chromosome 9; they observed the Nager syndrome in an infant with an
apparently balanced X;9 translocation 46,X,t(X;9)(p22.1;q32).
Dreyer et al. (1998) identified a novel zinc finger gene, termed ZFP37
(602951), that maps to chromosome 9q32 and encodes a putative
transcription factor expressed in several tissues including human fetal
cartilage. On the basis of its map location and expression pattern,
Dreyer et al. (1998) suggested ZFP37 as a candidate gene for Nager
acrofacial dysostosis.
Scapoli et al. (2003) described an infant with Nager syndrome and a
chromatid gap within band 3p14. The parents were unavailable for
karyotype analysis. The chromatid gap was interpreted as the expression
of the chromosomal fragile site FRA3B (601153), which is located at
3p14. Scapoli et al. (2003) noted that although FRA3B is the most highly
expressed common fragile site, its molecular basis and phenotypic effect
were unknown (Wang et al., 1999). No repeat motifs, such as
trinucleotide repeats, had been identified within FRA3B. The authors
pointed out, however, that FRA3B lies within the FHIT locus in both
mouse and human. The FHIT gene is frequently deleted in a variety of
human cancers.
MOLECULAR GENETICS
After exome sequencing in patients with the Nager type of acrofacial
dysostosis pointed to SF3B4 (605593) as a strong candidate gene, Bernier
et al. (2012) identified 18 different heterozygous SF3B4 mutations in 20
(57%) of 35 families affected by Nager syndrome (see, e.g.,
605593.0001-605593.0004). Because of overlap in features between Nager
syndrome and mandibulofacial dysostosis with microcephaly (MFDM;
610536), which is caused by mutation in the EFTUD2 gene (603892),
Bernier et al. (2012) analyzed EFTUD2 in AFD patients who were negative
for mutation in SF3B4 and identified a nonsense mutation in the EFTUD2
gene in 1 patient (603892.0006). In retrospect, the patient also had
microcephaly, suggesting that MFDM rather than Nager syndrome was the
appropriate diagnosis.
Czeschik et al. (2013) analyzed the SF3B4 gene in 12 patients with Nager
syndrome and identified heterozygous mutations in 7 (63.6%) (see, e.g.,
605593.0003 and 605593.0005). In the 4 cases in which parental DNA was
available, the mutation was confirmed to have arisen de novo. The only
significant difference between the mutation-positive and -negative
patients was the more frequent presence of midface hypoplasia/retrusion
in patients with SF3B43 mutations (p = 0.045). Czeschik et al. (2013)
also observed that more than half of both mutation-positive and
-negative patients exhibited anomalies of the feet and toes, a clinical
sign that had previously been considered a rare manifestation of Nager
syndrome.
HISTORY
Gobbel et al. (2005) examined a fetus, dating from the early 19th
century, in the Meckel anatomic collection at the University of Halle,
Germany, and observed mandibulofacial defects and preaxially malformed
limbs. Radiologic and CT examination showed complex facial malformations
with mandibular hypoplasia and dysgenesis of the ear capsule. The
ossified thorax was slender with ribs pointing downward, hypoplastic
claviculae, and ankylosis of the shoulder joint on both sides. Although
the upper limbs were of normal length, there was bilateral radial
agenesis with laterally convex diaphyses of the ulnae, left-sided
aplasia and right-sided hypoplasia of the thumbs, and bilateral club
hands. The right foot showed varus, adduction, and supination, while the
face of the left tibia rotated outward. Comparative genomic
hybridization analysis did not reveal any chromosomal imbalance. Gobbel
et al. (2005) stated that the Meckel specimen is likely the earliest
known fetus with Nager AFD.
*FIELD* SA
Bowen and Harley (1974); Fineman (1981); Gellis et al. (1978); Giugliani
and Pereira (1984); Krauss et al. (1985); Pfeiffer and Stoess (1983);
Thompson et al. (1985)
*FIELD* RF
1. Aylsworth, A. S.; Friedman, P. A.; Powers, S. K.; Kahler, S. G.
: New observations with genetic implications in two syndromes: (1)
father to son transmission of the Nager acrofacial dysostosis syndrome;
and (2) parental consanguinity in the Proteus syndrome. (Abstract) Am.
J. Hum. Genet. 41: A43 only, 1987.
2. Aylsworth, A. S.; Lin, A. E.: Male to male transmission in a second
family supports autosomal dominant inheritance in Nager acrofacial
dysostosis. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A47 only,
1990.
3. Aylsworth, A. S.; Lin, A. E.; Friedman, P. A.: Nager acrofacial
dysostosis: male-to-male transmission in 2 families. Am. J. Med.
Genet. 41: 83-88, 1991.
4. Bernier, F. P.; Caluseriu, O.; Ng, S.; Schwartzentruber, J.; Buckingham,
K. J.; Innes, A. M.; Jabs, E. W.; Innis, J. W.; Schuette, J. L.; Gorski,
J. L.; Byers, P. H.; Andelfinger, G.; and 12 others: Haploinsufficiency
of SF3B4, a component of the pre-mRNA spliceosomal complex, causes
Nager syndrome. Am. J. Hum. Genet. 90: 925-933, 2012.
5. Bonthron, D. T.; Macgregor, D. F.; Barr, D. G. D.: Nager acrofacial
dysostosis: minor familial manifestations supporting dominant inheritance. Clin.
Genet. 43: 127-131, 1993.
6. Bowen, P.; Harley, F.: Mandibulo-facial dysostosis with limb malformations
(Nager's acrofacial dysostosis). Birth Defects Orig. Art. Ser. X(5):
109-115, 1974.
7. Burton, B. K.; Nadler, H. L.: Nager acrofacial dysostosis: report
of a case. J. Pediat. 91: 84-86, 1977.
8. Byrd, L. K.; Rogers, R. C.; Stevenson, R. E.: Nager acrofacial
dysostosis in four patients including monozygous twins. Proc. Greenwood
Genet. Center 7: 30-35, 1988.
9. Chemke, J.; Mogilner, B. M.; Ben-Itzhak, I.; Zurkowski, L.; Ophir,
D.: Autosomal recessive inheritance of Nager acrofacial dysostosis. J.
Med. Genet. 25: 230-232, 1988.
10. Czeschik, J. C.; Voigt, C.; Alanay, Y.; Albrecht, B.; Avci, S.;
FitzPatrick, D.; Goudie, D. R.; Hehr, U.; Hoogeboom, A. J.; Kayserili,
H.; Simsek-Kiper, P. O.; Klein-Hitpass, L.; and 10 others: Clinical
and mutation data in 12 patients with the clinical diagnosis of Nager
syndrome. Hum. Genet. 132: 885-898, 2013.
11. Dreyer, S. D.; Zhou, L.; Machado, M. A.; Horton, W. A.; Zabel,
B.; Winterpacht, A.; Lee, B.: Cloning, characterization, and chromosomal
assignment of the human ortholog of murine Zfp-37, a candidate gene
for Nager syndrome. Mammalian Genome 9: 458-462, 1998.
12. Fineman, R. M.: Recurrence of the postaxial acrofacial dysostosis
syndrome in a sibship: implications for genetic counselling. J. Pediat. 98:
87-88, 1981.
13. Fryns, J. P.; Bonhomme, A.; van den Berghe, H.: Nager acrofacial
dysostosis: an adult male with severe neurological deficit. Genet.
Counsel. 7: 147-151, 1996.
14. Gellis, S. S.; Feingold, M.; Miller, D.: Nager's syndrome (Nager's
acrofacial dysostosis). Am. J. Dis. Child. 132: 519-520, 1978.
15. Giugliani, R.; Pereira, C. H.: Nager's acrofacial dysostosis
with thumb duplication: report of a case. Clin. Genet. 26: 228-230,
1984.
16. Gobbel, L.; Schultka, R.; Klunker, R.; Stock, K.; Wand, D.; Olsson,
L.; Gerlach, A.; Tonnies, H.: Acrofacial dysostosis (AFD) with preaxial
limb hypoplasia (Nager AFD) and club foot diagnosed in a fetus from
1812 in the anatomical collections at the University of Halle, Germany. Am.
J. Med. Genet. 137A: 263-268, 2005.
17. Goldstein, D. J.; Mirkin, L. D.: Nager acrofacial dysostosis:
evidence for apparent heterogeneity. Am. J. Med. Genet. 30: 741-746,
1988.
18. Halal, F.; Herrmann, J.; Pallister, P. D.; Opitz, J. M.; Desgranges,
M.-F.; Grenier, G.: Differential diagnosis of Nager acrofacial dysostosis
syndrome: report of four patients with Nager syndrome and discussion
of other related syndromes. Am. J. Med. Genet. 14: 209-224, 1983.
19. Hecht, J. T.; Immken, L. L.; Harris, L. F.; Malini, S.; Scott,
C. I., Jr.: The Nager syndrome. Am. J. Med. Genet. 27: 965-969,
1987.
20. Krauss, C. M.; Hassell, L. A.; Gang, D. L.: Anomalies in an infant
with Nager acrofacial dysostosis. Am. J. Med. Genet. 21: 761-764,
1985.
21. Lowry, R. B.: The Nager syndrome (acrofacial dysostosis): evidence
for autosomal dominant inheritance. Birth Defects Orig. Art. Ser. XIII(3C):
195-220, 1977.
22. Marden, P. M.; Smith, D. W.; McDonald, M. J.: Congenital anomalies
in the newborn infant, including minor variations: a study of 4,412
babies by surface examination for anomalies and buccal smear for sex
chromatin. J. Pediat. 64: 357-371, 1964.
23. McDonald, M. T.; Gorski, J. L.: Nager acrofacial dysostosis. J.
Med. Genet. 30: 779-782, 1993.
24. Nager, F. R.; de Reynier, J. P.: Das Gehoerorgan bei den angeborenen
Kopfmissbildungen. Pract. Otorhinolaryng. 10 (suppl. 2): 1-128,
1948.
25. Opitz, J. M.: Nager 'syndrome' versus 'anomaly' and its nosology
with the postaxial acrofacial dysostosis syndrome of Genee and Wiedemann. Am.
J. Med. Genet. 27: 959-963, 1987.
26. Palomeque, A.; Pastor, X.; Ballesta, F.: Nager anomaly with severe
facial involvement, microcephaly, and mental retardation. Am. J.
Med. Genet. 36: 356-357, 1990.
27. Pfeiffer, R. A.; Stoess, H.: Acrofacial dysostosis (Nager syndrome):
synopsis and report of a new case. Am. J. Med. Genet. 15: 255-260,
1983.
28. Richieri-Costa, A.; Gollop, T. R.; Colletto, G. M. D. D.: Syndrome
of acrofacial dysostosis, cleft lip/palate, and triphalangeal thumb
in a Brazilian family. Am. J. Med. Genet. 14: 225-229, 1983.
29. Scapoli, L.; Martinelli, M.; Pezzetti, F.; Carahelli, E.; Carinci,
F.; Cenzi, R.; Meneghetti, A.; Donti, E.: Spontaneous expression
of FRA3P in a patient with Nager syndrome. (Letter) Am. J. Med. Genet. 118A:
293-295, 2003.
30. Seller, H.: Dystrophia unguis mediana canaliformis: familiaeres
Vorkommen. Hautarzt 25: 456 only, 1974.
31. Slingenberg, B.: Misbildungen von Extremitaeten. Virchows Arch.
Path. Anat. 193: 1-92, 1908.
32. Thompson, E.; Cadbury, R.; Baraitser, M.: The Nager acrofacial
dysostosis syndrome with the tetralogy of Fallot. J. Med. Genet. 22:
408-410, 1985.
33. Waggoner, D. J.; Ciske, D. J.; Dowton, S. B.; Watson, M. S.:
Deletion of 1q in a patient with acrofacial dysostosis. Am. J. Med.
Genet. 82: 301-304, 1999.
34. Walker, F. A.: Apparent autosomal recessive inheritance of Treacher
Collins syndrome. Birth Defects Orig. Art. Ser. X(8): 135-139, 1974.
35. Wang, L.; Darling, J.; Zhang, J.-S.; Huang, H.; Liu, W.; Smith,
D. I.: Allele-specific late replication and fragility of the most
active fragile site, FRA3B. Hum. Molec. Genet. 8: 431-437, 1999.
36. Weinbaum, M.; Russell, L.; Bixler, D.: Autosomal dominant transmission
of Nager acrofacial dysostosis. (Abstract) Am. J. Hum. Genet. 33:
93A only, 1981.
37. Zori, R. T.; Gray, B. A.; Bent-Williams, A.; Driscoll, D. J.;
Williams, C. A.; Zackowski, J. L.: Preaxial acrofacial dysostosis
(Nager syndrome) associated with an inherited and apparently balanced
X;9 translocation: prenatal and postnatal late replication studies. Am.
J. Med. Genet. 46: 379-383, 1993.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
[Ears];
Conductive deafness;
Low-set ears;
Posteriorly rotated ears;
Preauricular tags;
External auditory canal atresia;
[Eyes];
Downslanting palpebral fissures;
Partial-total absence of lower eyelashes;
Lower lid coloboma;
[Nose];
High nasal bridge;
[Mouth];
Cleft palate;
Cleft lip;
Macrostomia;
Trismus;
Velopharyngeal insufficiency
CARDIOVASCULAR:
[Heart];
Tetralogy of Fallot
RESPIRATORY:
[Larynx];
Laryngeal hypoplasia;
[Airways];
Hypoplasia of the epiglottis
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Hypoplastic first rib
ABDOMEN:
[External features];
Gastroschisis;
[Gastrointestinal];
Hirschsprung disease
GENITOURINARY:
[Internal genitalia, female];
Bicornuate uterus;
[Kidneys];
Unilateral renal agenesis;
Duplicated calyx
SKELETAL:
[Skull];
Hypoplastic zygomatic arch;
Hypoplastic mandible;
[Spine];
Scoliosis;
Cervical vertebral abnormalities;
[Pelvis];
Hip dislocation;
[Limbs];
Radioulnar synostosis;
Limitation of elbow extension;
Short forearms;
Radial aplasia;
Radial hypoplasia;
[Hands];
Thumb aplasia/hypoplasia;
Syndactyly;
Clinodactyly;
Triphalangeal thumbs;
[Feet];
Missing toes;
Hypoplastic toes;
Toe syndactyly;
Overlapping toes;
Hallux valgus;
Broad hallux;
Clubfeet
SKIN, NAILS, HAIR:
[Skin];
Urticaria pigmentosa;
[Hair];
Partial to total absence of eyelashes
NEUROLOGIC:
[Central nervous system];
Normal intelligence;
Hydrocephalus;
Aqueductal stenosis;
Polymicrogyria;
Speech delay
PRENATAL MANIFESTATIONS:
[Delivery];
Premature birth
MISCELLANEOUS:
Most cases are sporadic
MOLECULAR BASIS:
Caused by mutation in the splicing factor 3B, subunit 4 gene (SF3B4,
605593.0001)
*FIELD* CN
Joanna S. Amberger - updated: 06/05/2012
Kelly A. Przylepa - revised: 3/1/2002
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 06/05/2012
joanna: 4/10/2012
joanna: 3/14/2005
joanna: 3/1/2002
*FIELD* CN
Marla J. F. O'Neill - updated: 9/18/2013
Marla J. F. O'Neill - updated: 6/4/2012
Marla J. F. O'Neill - updated: 10/3/2005
Victor A. McKusick - updated: 4/25/2003
Sonja A. Rasmussen - updated: 5/12/1999
Iosif W. Lurie - updated: 9/22/1996
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 10/08/2013
carol: 9/18/2013
carol: 6/5/2012
terry: 6/4/2012
carol: 7/15/2009
joanna: 2/2/2009
wwang: 9/16/2008
wwang: 10/10/2005
terry: 10/3/2005
terry: 7/31/2003
carol: 4/30/2003
tkritzer: 4/30/2003
terry: 4/25/2003
carol: 5/12/1999
carol: 6/26/1998
carol: 9/22/1996
mimadm: 11/6/1994
terry: 6/14/1994
carol: 1/27/1994
carol: 11/1/1993
carol: 10/29/1993
carol: 6/30/1993
*RECORD*
*FIELD* NO
154400
*FIELD* TI
#154400 ACROFACIAL DYSOSTOSIS 1, NAGER TYPE; AFD1
;;MANDIBULOFACIAL DYSOSTOSIS, TREACHER COLLINS TYPE, WITH LIMB ANOMALIES;;
read moreNAGER ACROFACIAL DYSOSTOSIS;;
AFD, NAGER TYPE;;
NAGER SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
Nager type of acrofacial dysostosis (AFD1) is caused by heterozygous
mutation in the SF3B4 gene (605593) on chromosome 1q12-q21.
DESCRIPTION
Nager syndrome is the prototype for a group of disorders collectively
referred to as the acrofacial dysostoses (AFDs), which are characterized
by malformation of the craniofacial skeleton and the limbs. The major
facial features of Nager syndrome include downslanted palpebral
fissures, midface retrusion, and micrognathia, the latter of which often
requires the placement of a tracheostomy in early childhood. Limb
defects typically involve the anterior (radial) elements of the upper
limbs and manifest as small or absent thumbs, triphalangeal thumbs,
radial hyoplasia or aplasia, and radioulnar synostosis. Phocomelia of
the upper limbs and, occasionally, lower-limb defects have also been
reported. The presence of anterior upper-limb defects and the typical
lack of lower-limb involvement distinguishes Nager syndrome from Miller
syndrome (263750), another rare AFD; however, distingushing Nager
syndrome from other AFDs, including Miller syndrome, can be challenging
(summary by Bernier et al., 2012).
CLINICAL FEATURES
Nager acrofacial dysostosis was recognized as a specific entity by Nager
and de Reynier (1948), but was probably first reported by Slingenberg
(1908). The limb deformities in the Nager syndrome consist of absence of
radius, radioulnar synostosis, and hypoplasia or absence of the thumbs.
The mandibulofacial dysostosis is characterized mainly by severe
micrognathia and malar hypoplasia.
The disorder reported by Walker (1974) in sibs whose parents were normal
may have been Nager syndrome.
Weinbaum et al. (1981) described a kindred in which the proband had
classic Nager syndrome and 5 other persons covering 4 generations showed
lesser expression. They suggested that ptosis of the lower lids,
hypoplasia of the lower lid eyelashes, and cartilaginous pegs between
the antitragus and lobule are minimal expressions of the syndrome.
Richieri-Costa et al. (1983) described 2 sisters, offspring of
nonconsanguineous parents, who had facial and skeletal anomalies. One
had mandibulofacial dysostosis with bilateral radial ray anomalies. The
other had cleft lip and palate with hypoplastic thumbs.
Halal et al. (1983) reported 4 patients and reviewed all previous cases.
This led to an extended characterization of Nager acrofacial dysostosis,
e.g., description of lower limb defects. The differentiation from AFD
with postaxial defects (263750), the hemifacial microsomia/Goldenhar
radial defect syndrome, and other syndromes was discussed.
Opitz (1987) suggested that Nager acrofacial dysostosis represents an
'anomaly' rather than a syndrome because of its apparent causal
heterogeneity.
Aylsworth et al. (1987) described findings in a father and child
consistent with the Nager syndrome and supporting autosomal dominant
inheritance. In addition to cranial features, the child had a small left
thumb and absence of the right thumb. The father had similar facial
features, a nonfunctional, proximally placed right thumb, and the
history of a rudimentary left thumb that was removed during childhood.
Aylsworth and Lin (1990) described an affected father and 2 sons. One of
the sons had Hirschsprung disease.
Goldstein and Mirkin (1988) described an unusually severe form.
Palomeque et al. (1990) also reported a severely affected patient.
Bonthron et al. (1993) reported the case of a girl with Nager acrofacial
dysostosis who had a maternal aunt and maternal great-grandfather with a
short distal phalanx of the thumb (type D brachydactyly) and a maternal
grandmother with a bilateral congenital anomaly of the thumbnails
referred to as dystrophia unguis mediana canaliformis (Seller, 1974).
The thumb in this case was longitudinally divided. The family was
presented as supporting dominant inheritance.
Fryns et al. (1996) reported an adult male who, in addition to typical
manifestations, had agenesis of the corpus callosum, strabismus,
equinovarus position of both feet, cryptorchidism, and blind-ending
fistula in the middle of the anoscrotal raphe. The patient died at the
age of 50 years from heart failure due to a complete atrioventricular
block.
McDonald and Gorski (1993) presented a summary of 76 previously reported
cases and added 2 new cases. Proximal radioulnar synostosis was found in
16 of 19 cases in whom appropriate studies were performed.
See 263750 for the Miller acrofacial syndrome in which postaxial limb
changes (rather than preaxial as in Nager syndrome) are associated with
facial dysostosis.
See split-hand deformity with mandibulofacial dysostosis (183700).
INHERITANCE
There is evidence of autosomal dominant and autosomal recessive
inheritance of Nager acrofacial dysostosis.
Marden et al. (1964) described an infant with this syndrome whose father
and mother were 42 and 41 years of age, respectively, at the time of his
birth, thus suggesting dominant mutation.
Lowry (1977) described the anomaly in a patient whose father and mother
were 44 and 38 years of age, respectively, at her birth, compatible with
new dominant mutation.
Burton and Nadler (1977) described a case in the offspring of first
cousins; the father was aged 37 years.
Aylsworth et al. (1987) described a family with affected father and
child and Aylsworth and Lin (1990) described a family with affected
father and 2 sons, supporting the notion that some cases are caused by
autosomal dominant mutations (Aylsworth et al., 1991).
Chemke et al. (1988) reported affected male and female sibs; the parents
were unrelated.
Byrd et al. (1988) described 4 patients with Nager acrofacial
dysostosis, including a pair of concordantly affected monozygotic twins.
McDonald and Gorski (1993) presented a summary of 76 previously reported
cases and added 2 new cases. They favored inheritance as a pleiotropic
disorder with markedly variable penetrance and expressivity, but granted
that the occurrence of affected sibs with normal parents suggested
genetic heterogeneity with the existence of an autosomal recessive form.
They found 5 families with normal parents and 2 affected sibs.
DIAGNOSIS
- Prenatal Diagnosis
Hecht et al. (1987) identified the Nager syndrome in a newborn infant
and in a subsequent sib by prenatal ultrasonography. They presented this
as evidence of autosomal recessive inheritance.
CYTOGENETICS
Waggoner et al. (1999) reported a case of Nager syndrome with deletion
of the heterochromatic block and adjacent euchromatin of chromosome 1q
([46,XY,del(1)(q12q21.1)] or [46,XY,del(1)q12q21.3]). The affected child
also had severe aortic stenosis and right pulmonary bronchial stenosis.
The authors suggested that the deleted 1q region may contain genes
crucial for normal limb, craniofacial, and/or cardiopulmonary
development.
- Genetic Heterogeneity of Nager Syndrome
Zori et al. (1993) suggested that the gene for this disorder may reside
on chromosome 9; they observed the Nager syndrome in an infant with an
apparently balanced X;9 translocation 46,X,t(X;9)(p22.1;q32).
Dreyer et al. (1998) identified a novel zinc finger gene, termed ZFP37
(602951), that maps to chromosome 9q32 and encodes a putative
transcription factor expressed in several tissues including human fetal
cartilage. On the basis of its map location and expression pattern,
Dreyer et al. (1998) suggested ZFP37 as a candidate gene for Nager
acrofacial dysostosis.
Scapoli et al. (2003) described an infant with Nager syndrome and a
chromatid gap within band 3p14. The parents were unavailable for
karyotype analysis. The chromatid gap was interpreted as the expression
of the chromosomal fragile site FRA3B (601153), which is located at
3p14. Scapoli et al. (2003) noted that although FRA3B is the most highly
expressed common fragile site, its molecular basis and phenotypic effect
were unknown (Wang et al., 1999). No repeat motifs, such as
trinucleotide repeats, had been identified within FRA3B. The authors
pointed out, however, that FRA3B lies within the FHIT locus in both
mouse and human. The FHIT gene is frequently deleted in a variety of
human cancers.
MOLECULAR GENETICS
After exome sequencing in patients with the Nager type of acrofacial
dysostosis pointed to SF3B4 (605593) as a strong candidate gene, Bernier
et al. (2012) identified 18 different heterozygous SF3B4 mutations in 20
(57%) of 35 families affected by Nager syndrome (see, e.g.,
605593.0001-605593.0004). Because of overlap in features between Nager
syndrome and mandibulofacial dysostosis with microcephaly (MFDM;
610536), which is caused by mutation in the EFTUD2 gene (603892),
Bernier et al. (2012) analyzed EFTUD2 in AFD patients who were negative
for mutation in SF3B4 and identified a nonsense mutation in the EFTUD2
gene in 1 patient (603892.0006). In retrospect, the patient also had
microcephaly, suggesting that MFDM rather than Nager syndrome was the
appropriate diagnosis.
Czeschik et al. (2013) analyzed the SF3B4 gene in 12 patients with Nager
syndrome and identified heterozygous mutations in 7 (63.6%) (see, e.g.,
605593.0003 and 605593.0005). In the 4 cases in which parental DNA was
available, the mutation was confirmed to have arisen de novo. The only
significant difference between the mutation-positive and -negative
patients was the more frequent presence of midface hypoplasia/retrusion
in patients with SF3B43 mutations (p = 0.045). Czeschik et al. (2013)
also observed that more than half of both mutation-positive and
-negative patients exhibited anomalies of the feet and toes, a clinical
sign that had previously been considered a rare manifestation of Nager
syndrome.
HISTORY
Gobbel et al. (2005) examined a fetus, dating from the early 19th
century, in the Meckel anatomic collection at the University of Halle,
Germany, and observed mandibulofacial defects and preaxially malformed
limbs. Radiologic and CT examination showed complex facial malformations
with mandibular hypoplasia and dysgenesis of the ear capsule. The
ossified thorax was slender with ribs pointing downward, hypoplastic
claviculae, and ankylosis of the shoulder joint on both sides. Although
the upper limbs were of normal length, there was bilateral radial
agenesis with laterally convex diaphyses of the ulnae, left-sided
aplasia and right-sided hypoplasia of the thumbs, and bilateral club
hands. The right foot showed varus, adduction, and supination, while the
face of the left tibia rotated outward. Comparative genomic
hybridization analysis did not reveal any chromosomal imbalance. Gobbel
et al. (2005) stated that the Meckel specimen is likely the earliest
known fetus with Nager AFD.
*FIELD* SA
Bowen and Harley (1974); Fineman (1981); Gellis et al. (1978); Giugliani
and Pereira (1984); Krauss et al. (1985); Pfeiffer and Stoess (1983);
Thompson et al. (1985)
*FIELD* RF
1. Aylsworth, A. S.; Friedman, P. A.; Powers, S. K.; Kahler, S. G.
: New observations with genetic implications in two syndromes: (1)
father to son transmission of the Nager acrofacial dysostosis syndrome;
and (2) parental consanguinity in the Proteus syndrome. (Abstract) Am.
J. Hum. Genet. 41: A43 only, 1987.
2. Aylsworth, A. S.; Lin, A. E.: Male to male transmission in a second
family supports autosomal dominant inheritance in Nager acrofacial
dysostosis. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A47 only,
1990.
3. Aylsworth, A. S.; Lin, A. E.; Friedman, P. A.: Nager acrofacial
dysostosis: male-to-male transmission in 2 families. Am. J. Med.
Genet. 41: 83-88, 1991.
4. Bernier, F. P.; Caluseriu, O.; Ng, S.; Schwartzentruber, J.; Buckingham,
K. J.; Innes, A. M.; Jabs, E. W.; Innis, J. W.; Schuette, J. L.; Gorski,
J. L.; Byers, P. H.; Andelfinger, G.; and 12 others: Haploinsufficiency
of SF3B4, a component of the pre-mRNA spliceosomal complex, causes
Nager syndrome. Am. J. Hum. Genet. 90: 925-933, 2012.
5. Bonthron, D. T.; Macgregor, D. F.; Barr, D. G. D.: Nager acrofacial
dysostosis: minor familial manifestations supporting dominant inheritance. Clin.
Genet. 43: 127-131, 1993.
6. Bowen, P.; Harley, F.: Mandibulo-facial dysostosis with limb malformations
(Nager's acrofacial dysostosis). Birth Defects Orig. Art. Ser. X(5):
109-115, 1974.
7. Burton, B. K.; Nadler, H. L.: Nager acrofacial dysostosis: report
of a case. J. Pediat. 91: 84-86, 1977.
8. Byrd, L. K.; Rogers, R. C.; Stevenson, R. E.: Nager acrofacial
dysostosis in four patients including monozygous twins. Proc. Greenwood
Genet. Center 7: 30-35, 1988.
9. Chemke, J.; Mogilner, B. M.; Ben-Itzhak, I.; Zurkowski, L.; Ophir,
D.: Autosomal recessive inheritance of Nager acrofacial dysostosis. J.
Med. Genet. 25: 230-232, 1988.
10. Czeschik, J. C.; Voigt, C.; Alanay, Y.; Albrecht, B.; Avci, S.;
FitzPatrick, D.; Goudie, D. R.; Hehr, U.; Hoogeboom, A. J.; Kayserili,
H.; Simsek-Kiper, P. O.; Klein-Hitpass, L.; and 10 others: Clinical
and mutation data in 12 patients with the clinical diagnosis of Nager
syndrome. Hum. Genet. 132: 885-898, 2013.
11. Dreyer, S. D.; Zhou, L.; Machado, M. A.; Horton, W. A.; Zabel,
B.; Winterpacht, A.; Lee, B.: Cloning, characterization, and chromosomal
assignment of the human ortholog of murine Zfp-37, a candidate gene
for Nager syndrome. Mammalian Genome 9: 458-462, 1998.
12. Fineman, R. M.: Recurrence of the postaxial acrofacial dysostosis
syndrome in a sibship: implications for genetic counselling. J. Pediat. 98:
87-88, 1981.
13. Fryns, J. P.; Bonhomme, A.; van den Berghe, H.: Nager acrofacial
dysostosis: an adult male with severe neurological deficit. Genet.
Counsel. 7: 147-151, 1996.
14. Gellis, S. S.; Feingold, M.; Miller, D.: Nager's syndrome (Nager's
acrofacial dysostosis). Am. J. Dis. Child. 132: 519-520, 1978.
15. Giugliani, R.; Pereira, C. H.: Nager's acrofacial dysostosis
with thumb duplication: report of a case. Clin. Genet. 26: 228-230,
1984.
16. Gobbel, L.; Schultka, R.; Klunker, R.; Stock, K.; Wand, D.; Olsson,
L.; Gerlach, A.; Tonnies, H.: Acrofacial dysostosis (AFD) with preaxial
limb hypoplasia (Nager AFD) and club foot diagnosed in a fetus from
1812 in the anatomical collections at the University of Halle, Germany. Am.
J. Med. Genet. 137A: 263-268, 2005.
17. Goldstein, D. J.; Mirkin, L. D.: Nager acrofacial dysostosis:
evidence for apparent heterogeneity. Am. J. Med. Genet. 30: 741-746,
1988.
18. Halal, F.; Herrmann, J.; Pallister, P. D.; Opitz, J. M.; Desgranges,
M.-F.; Grenier, G.: Differential diagnosis of Nager acrofacial dysostosis
syndrome: report of four patients with Nager syndrome and discussion
of other related syndromes. Am. J. Med. Genet. 14: 209-224, 1983.
19. Hecht, J. T.; Immken, L. L.; Harris, L. F.; Malini, S.; Scott,
C. I., Jr.: The Nager syndrome. Am. J. Med. Genet. 27: 965-969,
1987.
20. Krauss, C. M.; Hassell, L. A.; Gang, D. L.: Anomalies in an infant
with Nager acrofacial dysostosis. Am. J. Med. Genet. 21: 761-764,
1985.
21. Lowry, R. B.: The Nager syndrome (acrofacial dysostosis): evidence
for autosomal dominant inheritance. Birth Defects Orig. Art. Ser. XIII(3C):
195-220, 1977.
22. Marden, P. M.; Smith, D. W.; McDonald, M. J.: Congenital anomalies
in the newborn infant, including minor variations: a study of 4,412
babies by surface examination for anomalies and buccal smear for sex
chromatin. J. Pediat. 64: 357-371, 1964.
23. McDonald, M. T.; Gorski, J. L.: Nager acrofacial dysostosis. J.
Med. Genet. 30: 779-782, 1993.
24. Nager, F. R.; de Reynier, J. P.: Das Gehoerorgan bei den angeborenen
Kopfmissbildungen. Pract. Otorhinolaryng. 10 (suppl. 2): 1-128,
1948.
25. Opitz, J. M.: Nager 'syndrome' versus 'anomaly' and its nosology
with the postaxial acrofacial dysostosis syndrome of Genee and Wiedemann. Am.
J. Med. Genet. 27: 959-963, 1987.
26. Palomeque, A.; Pastor, X.; Ballesta, F.: Nager anomaly with severe
facial involvement, microcephaly, and mental retardation. Am. J.
Med. Genet. 36: 356-357, 1990.
27. Pfeiffer, R. A.; Stoess, H.: Acrofacial dysostosis (Nager syndrome):
synopsis and report of a new case. Am. J. Med. Genet. 15: 255-260,
1983.
28. Richieri-Costa, A.; Gollop, T. R.; Colletto, G. M. D. D.: Syndrome
of acrofacial dysostosis, cleft lip/palate, and triphalangeal thumb
in a Brazilian family. Am. J. Med. Genet. 14: 225-229, 1983.
29. Scapoli, L.; Martinelli, M.; Pezzetti, F.; Carahelli, E.; Carinci,
F.; Cenzi, R.; Meneghetti, A.; Donti, E.: Spontaneous expression
of FRA3P in a patient with Nager syndrome. (Letter) Am. J. Med. Genet. 118A:
293-295, 2003.
30. Seller, H.: Dystrophia unguis mediana canaliformis: familiaeres
Vorkommen. Hautarzt 25: 456 only, 1974.
31. Slingenberg, B.: Misbildungen von Extremitaeten. Virchows Arch.
Path. Anat. 193: 1-92, 1908.
32. Thompson, E.; Cadbury, R.; Baraitser, M.: The Nager acrofacial
dysostosis syndrome with the tetralogy of Fallot. J. Med. Genet. 22:
408-410, 1985.
33. Waggoner, D. J.; Ciske, D. J.; Dowton, S. B.; Watson, M. S.:
Deletion of 1q in a patient with acrofacial dysostosis. Am. J. Med.
Genet. 82: 301-304, 1999.
34. Walker, F. A.: Apparent autosomal recessive inheritance of Treacher
Collins syndrome. Birth Defects Orig. Art. Ser. X(8): 135-139, 1974.
35. Wang, L.; Darling, J.; Zhang, J.-S.; Huang, H.; Liu, W.; Smith,
D. I.: Allele-specific late replication and fragility of the most
active fragile site, FRA3B. Hum. Molec. Genet. 8: 431-437, 1999.
36. Weinbaum, M.; Russell, L.; Bixler, D.: Autosomal dominant transmission
of Nager acrofacial dysostosis. (Abstract) Am. J. Hum. Genet. 33:
93A only, 1981.
37. Zori, R. T.; Gray, B. A.; Bent-Williams, A.; Driscoll, D. J.;
Williams, C. A.; Zackowski, J. L.: Preaxial acrofacial dysostosis
(Nager syndrome) associated with an inherited and apparently balanced
X;9 translocation: prenatal and postnatal late replication studies. Am.
J. Med. Genet. 46: 379-383, 1993.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
[Ears];
Conductive deafness;
Low-set ears;
Posteriorly rotated ears;
Preauricular tags;
External auditory canal atresia;
[Eyes];
Downslanting palpebral fissures;
Partial-total absence of lower eyelashes;
Lower lid coloboma;
[Nose];
High nasal bridge;
[Mouth];
Cleft palate;
Cleft lip;
Macrostomia;
Trismus;
Velopharyngeal insufficiency
CARDIOVASCULAR:
[Heart];
Tetralogy of Fallot
RESPIRATORY:
[Larynx];
Laryngeal hypoplasia;
[Airways];
Hypoplasia of the epiglottis
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Hypoplastic first rib
ABDOMEN:
[External features];
Gastroschisis;
[Gastrointestinal];
Hirschsprung disease
GENITOURINARY:
[Internal genitalia, female];
Bicornuate uterus;
[Kidneys];
Unilateral renal agenesis;
Duplicated calyx
SKELETAL:
[Skull];
Hypoplastic zygomatic arch;
Hypoplastic mandible;
[Spine];
Scoliosis;
Cervical vertebral abnormalities;
[Pelvis];
Hip dislocation;
[Limbs];
Radioulnar synostosis;
Limitation of elbow extension;
Short forearms;
Radial aplasia;
Radial hypoplasia;
[Hands];
Thumb aplasia/hypoplasia;
Syndactyly;
Clinodactyly;
Triphalangeal thumbs;
[Feet];
Missing toes;
Hypoplastic toes;
Toe syndactyly;
Overlapping toes;
Hallux valgus;
Broad hallux;
Clubfeet
SKIN, NAILS, HAIR:
[Skin];
Urticaria pigmentosa;
[Hair];
Partial to total absence of eyelashes
NEUROLOGIC:
[Central nervous system];
Normal intelligence;
Hydrocephalus;
Aqueductal stenosis;
Polymicrogyria;
Speech delay
PRENATAL MANIFESTATIONS:
[Delivery];
Premature birth
MISCELLANEOUS:
Most cases are sporadic
MOLECULAR BASIS:
Caused by mutation in the splicing factor 3B, subunit 4 gene (SF3B4,
605593.0001)
*FIELD* CN
Joanna S. Amberger - updated: 06/05/2012
Kelly A. Przylepa - revised: 3/1/2002
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 06/05/2012
joanna: 4/10/2012
joanna: 3/14/2005
joanna: 3/1/2002
*FIELD* CN
Marla J. F. O'Neill - updated: 9/18/2013
Marla J. F. O'Neill - updated: 6/4/2012
Marla J. F. O'Neill - updated: 10/3/2005
Victor A. McKusick - updated: 4/25/2003
Sonja A. Rasmussen - updated: 5/12/1999
Iosif W. Lurie - updated: 9/22/1996
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 10/08/2013
carol: 9/18/2013
carol: 6/5/2012
terry: 6/4/2012
carol: 7/15/2009
joanna: 2/2/2009
wwang: 9/16/2008
wwang: 10/10/2005
terry: 10/3/2005
terry: 7/31/2003
carol: 4/30/2003
tkritzer: 4/30/2003
terry: 4/25/2003
carol: 5/12/1999
carol: 6/26/1998
carol: 9/22/1996
mimadm: 11/6/1994
terry: 6/14/1994
carol: 1/27/1994
carol: 11/1/1993
carol: 10/29/1993
carol: 6/30/1993
MIM
605593
*RECORD*
*FIELD* NO
605593
*FIELD* TI
*605593 SPLICING FACTOR 3B, SUBUNIT 4; SF3B4
;;SF3B, 49-KD SUBUNIT; SF3B49;;
SPLICEOSOME-ASSOCIATED PROTEIN, 49-KD; SAP49
read more*FIELD* TX
For background information on the SF3B proteins, see SF3B1 (605590).
CLONING
By SDS-PAGE fractionation of spliceosomal proteins, micropeptide
sequence analysis, PCR with degenerate primers, and cDNA library
screening, Champion-Arnaud and Reed (1994) isolated a cDNA encoding
SF3B4, which they called SAP49. Sequence analysis predicted that the
424-amino acid protein contains 2 well-conserved RNA-recognition motifs
(RRM) in its N terminus and that the remainder of the protein is highly
proline and glycine rich. Northern blot analysis detected a 2.0-kb
transcript in HeLa cells. Western blot analysis confirmed that the
translated cDNA, like the native protein, has a molecular mass of 49 kD.
GENE FUNCTION
Using Farwestern blot analysis, Champion-Arnaud and Reed (1994) showed
that SF3B4 interacts directly with SF3B2 (605591) through its RRM rather
than its proline-rich domain. Champion Arnaud and Reed (1994) determined
that SF3B4 cross-links to a 29-nucleotide region in pre-mRNA near the
branch-point sequence in the A complex.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the SF3B4
gene to chromosome 1 (TMAP L35013).
MOLECULAR GENETICS
After exome sequencing in patients with the Nager type of acrofacial
dysostosis (AFD1; 154400) pointed to SF3B4 as a strong candidate gene,
Bernier et al. (2012) identified 18 different heterozygous SF3B4
mutations in 20 (57%) of 35 families affected by Nager syndrome (see,
e.g., 605593.0001-605593.0004).
*FIELD* AV
.0001
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, MET1VAL
In an affected mother and son and a father and 2 sons from 2 unrelated
families with the Nager type of acrofacial dysostosis (AFD1; 154400),
and in 1 sporadic patient, Bernier et al. (2012) identified
heterozygosity for a 1A-G transition in the initiation codon of the
SF3B4 gene, causing a met1-to-val (M1V) substitution predicted to result
in loss of the initiator methionine. The mutation was not found in more
than 10,800 chromosomes in the NHLBI exome sequencing project.
.0002
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, 1-BP INS, 1147C
In a mother and son with the Nager type of acrofacial dysostosis (AFD1;
154400), Bernier et al. (2012) identified heterozygosity for a 1-bp
insertion (1147dupC) in exon 6 of the SF3B4 gene, causing a frameshift
predicted to result in a premature termination codon (His383Profs*103).
The mutation was not found in more than 10,800 chromosomes in the NHLBI
exome sequencing project.
.0003
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, 1-BP DEL, 1147C
In a 2-year-old boy with the Nager type of acrofacial dysostosis (AFD1;
154400), Bernier et al. (2012) identified heterozygosity for a 1-bp
deletion (1147delC) in exon 6 of the SF3B4 gene, causing a frameshift
predicted to result in a premature termination codon
(His383ProfsTer103). The mutation was not found in more than 10,800
chromosomes in the NHLBI exome sequencing project. Additional
malformations in this patient included fused first and second right
metacarpals and bilateral foot deformities.
In a male infant with Nager acrofacial dysostosis who died at birth due
to diaphragmatic hernia and lung hypoplasia, Czeschik et al. (2013)
identified heterozygosity for a de novo 1147C deletion in the SF3B4
gene.
.0004
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, IVS4, G-A, +1
In a 24-year-old woman with the Nager type of acrofacial dysostosis
(AFD1; 154400), Bernier et al. (2012) identified heterozygosity for a
G-A transition in intron 4 (913+1G-A) of the SF3B4 gene, predicted to
disrupt normal splicing. The mutation was not found in more than 10,800
chromosomes in the NHLBI exome sequencing project. Additional
malformations in this patient included abnormal teeth, partial absence
of left fingers 3 through 5, slender halluces, and hallux valgus.
.0005
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, ARG336TER
In a 13-year-old boy with the Nager type of acrofacial dysostosis
(154400), Czeschik et al. (2013) identified heterozygosity for a
c.1006C-T transition in exon 5 of the SF3B4 gene, resulting in an
arg336-to-ter (R336X) substitution. Czeschik et al. (2013) noted that
the R336X mutation had previously been reported in a patient with Nager
syndrome by Bernier et al. (2012).
*FIELD* RF
1. Bernier, F. P.; Caluseriu, O.; Ng, S.; Schwartzentruber, J.; Buckingham,
K. J.; Innes, A. M.; Jabs, E. W.; Innis, J. W.; Schuette, J. L.; Gorski,
J. L.; Byers, P. H.; Andelfinger, G.; and 12 others: Haploinsufficiency
of SF3B4, a component of the pre-mRNA spliceosomal complex, causes
Nager syndrome. Am. J. Hum. Genet. 90: 925-933, 2012.
2. Champion-Arnaud, P.; Reed, R.: The prespliceosome components SAP
49 and SAP 145 interact in a complex implicated in tethering U2 snRNP
to the branch site. Genes Dev. 8: 1974-1983, 1994.
3. Czeschik, J. C.; Voigt, C.; Alanay, Y.; Albrecht, B.; Avci, S.;
FitzPatrick, D.; Goudie, D. R.; Hehr, U.; Hoogeboom, A. J.; Kayserili,
H.; Simsek-Kiper, P. O.; Klein-Hitpass, L.; and 10 others: Clinical
and mutation data in 12 patients with the clinical diagnosis of Nager
syndrome. Hum. Genet. 132: 885-898, 2013.
*FIELD* CN
Marla J. F. O'Neill - updated: 09/18/2013
Marla J. F. O'Neill - updated: 6/4/2012
*FIELD* CD
Paul J. Converse: 1/26/2001
*FIELD* ED
carol: 09/18/2013
carol: 6/5/2012
terry: 6/4/2012
carol: 11/17/2008
mgross: 1/26/2001
*RECORD*
*FIELD* NO
605593
*FIELD* TI
*605593 SPLICING FACTOR 3B, SUBUNIT 4; SF3B4
;;SF3B, 49-KD SUBUNIT; SF3B49;;
SPLICEOSOME-ASSOCIATED PROTEIN, 49-KD; SAP49
read more*FIELD* TX
For background information on the SF3B proteins, see SF3B1 (605590).
CLONING
By SDS-PAGE fractionation of spliceosomal proteins, micropeptide
sequence analysis, PCR with degenerate primers, and cDNA library
screening, Champion-Arnaud and Reed (1994) isolated a cDNA encoding
SF3B4, which they called SAP49. Sequence analysis predicted that the
424-amino acid protein contains 2 well-conserved RNA-recognition motifs
(RRM) in its N terminus and that the remainder of the protein is highly
proline and glycine rich. Northern blot analysis detected a 2.0-kb
transcript in HeLa cells. Western blot analysis confirmed that the
translated cDNA, like the native protein, has a molecular mass of 49 kD.
GENE FUNCTION
Using Farwestern blot analysis, Champion-Arnaud and Reed (1994) showed
that SF3B4 interacts directly with SF3B2 (605591) through its RRM rather
than its proline-rich domain. Champion Arnaud and Reed (1994) determined
that SF3B4 cross-links to a 29-nucleotide region in pre-mRNA near the
branch-point sequence in the A complex.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the SF3B4
gene to chromosome 1 (TMAP L35013).
MOLECULAR GENETICS
After exome sequencing in patients with the Nager type of acrofacial
dysostosis (AFD1; 154400) pointed to SF3B4 as a strong candidate gene,
Bernier et al. (2012) identified 18 different heterozygous SF3B4
mutations in 20 (57%) of 35 families affected by Nager syndrome (see,
e.g., 605593.0001-605593.0004).
*FIELD* AV
.0001
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, MET1VAL
In an affected mother and son and a father and 2 sons from 2 unrelated
families with the Nager type of acrofacial dysostosis (AFD1; 154400),
and in 1 sporadic patient, Bernier et al. (2012) identified
heterozygosity for a 1A-G transition in the initiation codon of the
SF3B4 gene, causing a met1-to-val (M1V) substitution predicted to result
in loss of the initiator methionine. The mutation was not found in more
than 10,800 chromosomes in the NHLBI exome sequencing project.
.0002
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, 1-BP INS, 1147C
In a mother and son with the Nager type of acrofacial dysostosis (AFD1;
154400), Bernier et al. (2012) identified heterozygosity for a 1-bp
insertion (1147dupC) in exon 6 of the SF3B4 gene, causing a frameshift
predicted to result in a premature termination codon (His383Profs*103).
The mutation was not found in more than 10,800 chromosomes in the NHLBI
exome sequencing project.
.0003
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, 1-BP DEL, 1147C
In a 2-year-old boy with the Nager type of acrofacial dysostosis (AFD1;
154400), Bernier et al. (2012) identified heterozygosity for a 1-bp
deletion (1147delC) in exon 6 of the SF3B4 gene, causing a frameshift
predicted to result in a premature termination codon
(His383ProfsTer103). The mutation was not found in more than 10,800
chromosomes in the NHLBI exome sequencing project. Additional
malformations in this patient included fused first and second right
metacarpals and bilateral foot deformities.
In a male infant with Nager acrofacial dysostosis who died at birth due
to diaphragmatic hernia and lung hypoplasia, Czeschik et al. (2013)
identified heterozygosity for a de novo 1147C deletion in the SF3B4
gene.
.0004
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, IVS4, G-A, +1
In a 24-year-old woman with the Nager type of acrofacial dysostosis
(AFD1; 154400), Bernier et al. (2012) identified heterozygosity for a
G-A transition in intron 4 (913+1G-A) of the SF3B4 gene, predicted to
disrupt normal splicing. The mutation was not found in more than 10,800
chromosomes in the NHLBI exome sequencing project. Additional
malformations in this patient included abnormal teeth, partial absence
of left fingers 3 through 5, slender halluces, and hallux valgus.
.0005
ACROFACIAL DYSOSTOSIS 1, NAGER TYPE
SF3B4, ARG336TER
In a 13-year-old boy with the Nager type of acrofacial dysostosis
(154400), Czeschik et al. (2013) identified heterozygosity for a
c.1006C-T transition in exon 5 of the SF3B4 gene, resulting in an
arg336-to-ter (R336X) substitution. Czeschik et al. (2013) noted that
the R336X mutation had previously been reported in a patient with Nager
syndrome by Bernier et al. (2012).
*FIELD* RF
1. Bernier, F. P.; Caluseriu, O.; Ng, S.; Schwartzentruber, J.; Buckingham,
K. J.; Innes, A. M.; Jabs, E. W.; Innis, J. W.; Schuette, J. L.; Gorski,
J. L.; Byers, P. H.; Andelfinger, G.; and 12 others: Haploinsufficiency
of SF3B4, a component of the pre-mRNA spliceosomal complex, causes
Nager syndrome. Am. J. Hum. Genet. 90: 925-933, 2012.
2. Champion-Arnaud, P.; Reed, R.: The prespliceosome components SAP
49 and SAP 145 interact in a complex implicated in tethering U2 snRNP
to the branch site. Genes Dev. 8: 1974-1983, 1994.
3. Czeschik, J. C.; Voigt, C.; Alanay, Y.; Albrecht, B.; Avci, S.;
FitzPatrick, D.; Goudie, D. R.; Hehr, U.; Hoogeboom, A. J.; Kayserili,
H.; Simsek-Kiper, P. O.; Klein-Hitpass, L.; and 10 others: Clinical
and mutation data in 12 patients with the clinical diagnosis of Nager
syndrome. Hum. Genet. 132: 885-898, 2013.
*FIELD* CN
Marla J. F. O'Neill - updated: 09/18/2013
Marla J. F. O'Neill - updated: 6/4/2012
*FIELD* CD
Paul J. Converse: 1/26/2001
*FIELD* ED
carol: 09/18/2013
carol: 6/5/2012
terry: 6/4/2012
carol: 11/17/2008
mgross: 1/26/2001