RBCC Red Blood Cell Collection

RAB3GAP1 (KIAA0066, RAB3GAP) [Confidence: low (only semi-automatic identification from reviews)]
Rab3 GTPase-activating protein catalytic subunit (RAB3 GTPase-activating protein 130 kDa subunit; Rab3-GAP p130; Rab3-GAP)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q15042
ID RB3GP_HUMAN Reviewed; 981 AA.
AC Q15042; Q659F5; Q8TBB4;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 94.
DE RecName: Full=Rab3 GTPase-activating protein catalytic subunit;
DE AltName: Full=RAB3 GTPase-activating protein 130 kDa subunit;
DE AltName: Full=Rab3-GAP p130;
DE Short=Rab3-GAP;
GN Name=RAB3GAP1; Synonyms=KIAA0066, RAB3GAP;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S.,
RA Seki N., Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II.
RT The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 439-981, AND VARIANT
RP SER-598.
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 [4]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=9030515; DOI=10.1074/jbc.272.8.4655;
RA Fukui K., Sasaki T., Imazumi K., Matsuura Y., Nakanishi H., Takai Y.;
RT "Isolation and characterization of a GTPase activating protein
RT specific for the Rab3 subfamily of small G proteins.";
RL J. Biol. Chem. 272:4655-4658(1997).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=9852129; DOI=10.1074/jbc.273.51.34580;
RA Oishi H., Sasaki T., Nagano F., Ikeda W., Ohya T., Wada M., Ide N.,
RA Nakanishi H., Takai Y.;
RT "Localization of the Rab3 small G protein regulators in nerve
RT terminals and their involvement in Ca2+-dependent exocytosis.";
RL J. Biol. Chem. 273:34580-34585(1998).
RN [6]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF ARG-619;
RP ARG-700; ARG-728 AND ARG-753.
RX PubMed=10859313; DOI=10.1074/jbc.M003705200;
RA Clabecq A., Henry J.-P., Darchen F.;
RT "Biochemical characterization of Rab3-GTPase-activating protein
RT reveals a mechanism similar to that of Ras-GAP.";
RL J. Biol. Chem. 275:31786-31791(2000).
RN [7]
RP INVOLVEMENT IN WARBM1.
RX PubMed=15696165; DOI=10.1038/ng1517;
RA Aligianis I.A., Johnson C.A., Gissen P., Chen D., Hampshire D.,
RA Hoffmann K., Maina E.N., Morgan N.V., Tee L., Morton J.,
RA Ainsworth J.R., Horn D., Rosser E., Cole T.R.P., Stolte-Dijkstra I.,
RA Fieggen K., Clayton-Smith J., Megarbane A., Shield J.P.,
RA Newbury-Ecob R., Dobyns W.B., Graham J.M., Kjaer K.W., Warburg M.,
RA Bond J., Trembath R.C., Harris L.W., Takai Y., Mundlos S.,
RA Tannahill D., Woods C.G., Maher E.R.;
RT "Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro
RT syndrome.";
RL Nat. Genet. 37:221-223(2005).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
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).
CC -!- FUNCTION: Probable catalytic subunit of a GTPase activating
CC protein that has specificity for Rab3 subfamily (RAB3A, RAB3B,
CC RAB3C and RAB3D). Rab3 proteins are involved in regulated
CC exocytosis of neurotransmitters and hormones. Specifically
CC converts active Rab3-GTP to the inactive form Rab3-GDP. Required
CC for normal eye and brain development. May participate in
CC neurodevelopmental processes such as proliferation, migration and
CC differentiation before synapse formation, and non-synaptic
CC vesicular release of neurotransmitters.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=75 uM for GTP-loaded RAB3A;
CC -!- SUBUNIT: The Rab3 GTPase-activating complex is a heterodimer
CC composed of RAB3GAP and RAB3-GAP150. The Rab3 GTPase-activating
CC complex interacts with DMXL2 (By similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=In neurons, it is enriched
CC in the synaptic soluble fraction.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q15042-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15042-2; Sequence=VSP_013316, VSP_013317;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Warburg micro syndrome 1 (WARBM1) [MIM:600118]: A rare
CC syndrome characterized by microcephaly, microphthalmia,
CC microcornia, congenital cataracts, optic atrophy, cortical
CC dysplasia, in particular corpus callosum hypoplasia, severe mental
CC retardation, spastic diplegia, and hypogonadism. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the Rab3-GAP catalytic subunit family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAH56411.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RAB3GAP1";
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DR EMBL; D31886; BAA06684.1; -; mRNA.
DR EMBL; AL096752; CAH56411.1; ALT_INIT; mRNA.
DR EMBL; BC022977; AAH22977.1; -; mRNA.
DR RefSeq; NP_036365.1; NM_012233.2.
DR UniGene; Hs.306327; -.
DR ProteinModelPortal; Q15042; -.
DR IntAct; Q15042; 2.
DR STRING; 9606.ENSP00000264158; -.
DR PhosphoSite; Q15042; -.
DR DMDM; 62511099; -.
DR PaxDb; Q15042; -.
DR PRIDE; Q15042; -.
DR Ensembl; ENST00000264158; ENSP00000264158; ENSG00000115839.
DR GeneID; 22930; -.
DR KEGG; hsa:22930; -.
DR UCSC; uc002tuj.3; human.
DR CTD; 22930; -.
DR GeneCards; GC02P135809; -.
DR HGNC; HGNC:17063; RAB3GAP1.
DR HPA; HPA034495; -.
DR MIM; 600118; phenotype.
DR MIM; 602536; gene.
DR neXtProt; NX_Q15042; -.
DR Orphanet; 1387; Cataract - intellectual deficit - hypogonadism.
DR Orphanet; 2510; Micro syndrome.
DR PharmGKB; PA134969639; -.
DR eggNOG; NOG307494; -.
DR HOGENOM; HOG000253924; -.
DR HOVERGEN; HBG079116; -.
DR InParanoid; Q15042; -.
DR PhylomeDB; Q15042; -.
DR ChiTaRS; RAB3GAP1; human.
DR GeneWiki; RAB3GAP1; -.
DR GenomeRNAi; 22930; -.
DR NextBio; 43655; -.
DR PRO; PR:Q15042; -.
DR ArrayExpress; Q15042; -.
DR Bgee; Q15042; -.
DR CleanEx; HS_RAB3GAP1; -.
DR Genevestigator; Q15042; -.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005097; F:Rab GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0043010; P:camera-type eye development; IMP:BHF-UCL.
DR GO; GO:0060325; P:face morphogenesis; IMP:BHF-UCL.
DR GO; GO:0021854; P:hypothalamus development; IMP:BHF-UCL.
DR InterPro; IPR026147; Rab3-GAP_cat_su.
DR PANTHER; PTHR21422; PTHR21422; 1.
DR Pfam; PF13890; Rab3-GTPase_cat; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Cytoplasm; GTPase activation;
KW Polymorphism; Reference proteome.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 981 Rab3 GTPase-activating protein catalytic
FT subunit.
FT /FTId=PRO_0000191655.
FT VAR_SEQ 1 906 Missing (in isoform 2).
FT /FTId=VSP_013316.
FT VAR_SEQ 972 981 GAFSSDTSFF -> VKIIDGDV (in isoform 2).
FT /FTId=VSP_013317.
FT VARIANT 598 598 N -> S (in dbSNP:rs10445686).
FT /FTId=VAR_051716.
FT MUTAGEN 619 619 R->A: No effect.
FT MUTAGEN 700 700 R->A: No effect.
FT MUTAGEN 728 728 R->A: Loss of function.
FT MUTAGEN 753 753 R->A: No effect.
SQ SEQUENCE 981 AA; 110524 MW; 0673611C5C49641C CRC64;
MAADSEPESE VFEITDFTTA SEWERFISKV EEVLNDWKLI GNSLGKPLEK GIFTSGTWEE
KSDEISFADF KFSVTHHYLV QESTDKEGKD ELLEDVVPQS MQDLLGMNND FPPRAHCLVR
WYGLREFVVI APAAHSDAVL SESKCNLLLS SVSIALGNTG CQVPLFVQIH HKWRRMYVGE
CQGPGVRTDF EMVHLRKVPN QYTHLSGLLD IFKSKIGCPL TPLPPVSIAI RFTYVLQDWQ
QYFWPQQPPD IDALVGGEVG GLEFGKLPFG ACEDPISELH LATTWPHLTE GIIVDNDVYS
DLDPIQAPHW SVRVRKAENP QCLLGDFVTE FFKICRRKES TDEILGRSAF EEEGKETADI
THALSKLTEP ASVPIHKLSV SNMVHTAKKK IRKHRGVEES PLNNDVLNTI LLFLFPDAVS
EKPLDGTTST DNNNPPSESE DYNLYNQFKS APSDSLTYKL ALCLCMINFY HGGLKGVAHL
WQEFVLEMRF RWENNFLIPG LASGPPDLRC CLLHQKLQML NCCIERKKAR DEGKKTSASD
VTNIYPGDAG KAGDQLVPDN LKETDKEKGE VGKSWDSWSD SEEEFFECLS DTEELKGNGQ
ESGKKGGPKE MANLRPEGRL YQHGKLTLLH NGEPLYIPVT QEPAPMTEDL LEEQSEVLAK
LGTSAEGAHL RARMQSACLL SDMESFKAAN PGCSLEDFVR WYSPRDYIEE EVIDEKGNVV
LKGELSARMK IPSNMWVEAW ETAKPIPARR QRRLFDDTRE AEKVLHYLAI QKPADLARHL
LPCVIHAAVL KVKEEESLEN ISSVKKIIKQ IISHSSKVLH FPNPEDKKLE EIIHQITNVE
ALIARARSLK AKFGTEKCEQ EEEKEDLERF VSCLLEQPEV LVTGAGRGHA GRIIHKLFVN
AQRAAAMTPP EEELKRMGSP EERRQNSVSD FPPPAGREFI LRTTVPRPAP YSKALPQRMY
SVLTKEDFRL AGAFSSDTSF F
//

MIM 600118
*RECORD*
*FIELD* NO
600118
*FIELD* TI
#600118 WARBURG MICRO SYNDROME 1; WARBM1
;;MICRO SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because Warburg Micro
read moresyndrome-1 (WARBM1) can be caused by homozygous mutation in the RAB3GAP1
gene (602536) on chromosome 2q21.3.

DESCRIPTION

Warburg Micro syndrome is a rare autosomal recessive syndrome
characterized by microcephaly, microphthalmia, microcornea, congenital
cataracts, optic atrophy, cortical dysplasia, in particular corpus
callosum hypoplasia, severe mental retardation, spastic diplegia, and
hypogonadism (summary by Morris-Rosendahl et al., 2010).

- Genetic Heterogeneity of Warburg Micro Syndrome

Also see WARBM2 (614225), caused by mutation in the RAB3GAP2 gene
(609275) on chromosome 1q41, and WARBM3 (614222), caused by mutation in
the RAB18 gene (602207) on chromosome 10p12.1.

CLINICAL FEATURES

Warburg et al. (1993) used the designation Micro syndrome for an
autosomal recessive syndrome comprising microcephaly, microcornea,
congenital cataract, mental retardation, optic atrophy, and
hypogenitalism. They described an affected brother and sister and their
male cousin. The sibs were offspring of a consanguineous Pakistani
marriage; the parents of the cousin denied consanguinity. Agenesis of
the corpus callosum, prominent root of the nose, large anteverted ears,
facial hypertrichosis, small pupils with posterior synechiae, hypotonia,
mild to moderate spastic palsy with hip dislocations, and hormonal
dysfunction, presumably of hypothalamic origin, were other features. The
children were almost blind, whether or not the cataracts had been
operated on. The electroretinographic responses indicated dysfunction of
both retinal rods and cones, and the visual evoked potentials confirmed
optic nerve atrophy. The children were late walkers and were incontinent
of urine and stools. In the differential diagnosis, Warburg et al.
(1993) considered COFS syndrome (214150), CAMAK/CAMFAK syndromes
(212540), Martsolf syndrome (212720), lethal Rutledge syndrome (270400),
and lethal Neu-Laxova syndrome (256520).

Cases similar in nature to the phenotype designated 'Micro syndrome' by
Warburg et al. (1993) had previously been described. Sjogren and Larsson
(1949) reported 5 unrelated patients, 2 males and 3 females, with
microphthalmia, mental retardation, and spastic diplegia. Additional
ocular features included cataract in 2 patients, retino-choroiditis in
1, and degeneration of the retina in 1. Three of the patients also had
epilepsy. Pinsky et al. (1965) described 3 sisters with microcephaly,
microphthalmia, corneal opacity, severe mental retardation, spastic
cerebral palsy, and seizures. None had cataract or coloboma, although 2
had pupillary abnormalities. Their mother had unilateral microphthalmia
and was of normal intelligence. Balci et al. (1974) reported a
2-year-old girl, born of first-cousin parents, who had microcephaly,
microphthalmia, diffuse corneal opacity, mental retardation, generalized
muscular spasticity, and seizures. Urine chromatograms indicated
significant glycinuria and a large glycine spot was detected by blood
analysis.

Megarbane et al. (1999) reported 4 children from a highly inbred Shiite
Muslim family from southern Lebanon with hypotonia, spastic diplegia,
microcephaly, microphthalmia, congenital cataract, optic atrophy,
ptosis, kyphoscoliosis, short stature, severe mental retardation, and
cerebral malformations. Six other children in the kindred were probably
also affected. Megarbane et al. (1999) considered a number of possible
diagnoses, but thought that the phenotype of this family most closely
resembled that of Warburg Micro syndrome.

Rodriguez Criado et al. (1999) reported 2 sisters, born to unrelated
parents, who displayed microcephaly, microphthalmia, microcorneas,
cataracts, sparse medial eyebrows, micrognathia, and severe psychomotor
retardation. Cerebral MRI in both showed subcortical atrophy with large
ventricles, bilateral frontoparietal and insula cortical dysplasia, and
hypoplasia of the corpus callosum and the vermis with a large cisterna
magna. At 14 and 4 years of age, respectively, neither girl could speak
or stand, and neither had sphincter control. Rodriguez Criado et al.
(1999) noted that their patients had features similar to those
originally described by Warburg et al. (1993) but had a different facial
dysmorphism.

Ainsworth et al. (2001) studied 14 children with Micro syndrome, all
from consanguineous families, and identified several consistent
ophthalmic findings that they proposed might be pathognomonic for the
syndrome: microphthalmos, microphakia, cataract, atonic pupils, mild
optic atrophy, and severe cortical vision impairment. In addition, they
noted that all of their patients had marked microcephaly within the
first few months of life, hypotonia, spasticity within the first year of
life, and severe global developmental delay. MRI revealed variable
development of the corpus callosum, ranging from marked hypogenesis to
normal in 1 patient; all images demonstrated some degree of pachygyria.
Only some of the patients displayed the subtle dysmorphic facial
features described by Warburg et al. (1993).

Derbent et al. (2004) reported a 7-month-old male, born to first-cousin
Turkish parents, who had bilateral lens opacity and unresponsive pupils,
low-set and posteriorly angulated ears, broad nasal root and beaked
nose, long philtrum, micrognathia, and high-arched palate. He also had
bilateral cryptorchidism and micropenis, mental delay, truncal
hypotonia, and increased muscle tone in both legs. MRI revealed
hypoplasia of the corpus callosum, diffuse cortical and subcortical
atrophy, reduced myelinization, enlarged cisterna magna, and small
orbits. An unusual finding in this patient was fusion of the lower poles
of the kidneys and an ectopic left kidney.

Graham et al. (2004) described 3 pairs of affected sibs, including 1
pair with consanguineous parents, who were born with microcephaly,
microcornea, and cataracts.

Abdel-Salam et al. (2007) described 7 Egyptian patients (5 males and 2
females) from 5 families with microcephaly, mild microphthalmia,
microcornea, congenital cataracts, and hypogenitalism (only in males).
Facial features were consistent with those originally described in the
Micro syndrome in 3 patients; the remainder of the patients had facies
similar to those described in Martsolf syndrome. The patients had a
variable degree of brain atrophy, but hypogenesis of the corpus callosum
was evident only in 5 patients. Abnormal gyral pattern, small
cerebellum, vermian hypoplasia, and delayed myelination were additional
imaging findings in 3 cases. All patients had delayed visual evoked
potential but normal electroretinogram.

Yuksel et al. (2007) reported a 4-year-old boy with Warburg Micro
syndrome, the offspring of first-cousin Turkish parents, who had the
additional features of skin hyperextensibility, joint hypermobility,
deformities of metatarsals in both feet, and overlapping toes.

Morris-Rosendahl et al. (2010) studied 7 patients with Warburg Micro
syndrome from 5 families, all of whom had homozygous RAB3GAP1 (602536)
mutations. Features that were consistently found in these patients
included postnatal microcephaly, microphthalmia, microcornea, bilateral
congenital cataracts, short palpebral fissures, optic atrophy, severe
mental retardation, and congenital hypotonia with subsequent spasticity.
Only 1 patient had microcephaly at birth. Analysis of brain MRIs
revealed a consistent pattern of polymicrogyria in the frontal and
parietal lobes, wide sylvian fissures, a thin hypoplastic corpus
callosum, and increased subdural spaces.

DIAGNOSIS

Graham et al. (2004) pointed out that a prenatal viral infection should
be ruled out before considering mendelian origins for Micro syndrome.
Nucleotide excision repair (NER) studies in cultured fibroblasts can be
used to distinguish patients with Micro syndrome from those with COFS
syndrome or Cockayne syndrome (see 216400), because the latter
demonstrate hypersensitivity to ultraviolet radiation, whereas patients
with Micro syndrome have normal results. Graham et al. (2004) stated
that Micro syndrome can be distinguished from other similar clinical
disorders with normal NER by the presence of significant visual
impairment and cortical blindness despite early surgery for congenital
cataracts, frontal polymicrogyria, thin corpus callosum, and cortical
atrophy on MRI.

MAPPING

Aligianis et al. (2005) carried out a 10-cM genomewide scan in 12
individuals with Warburg Micro syndrome from 8 consanguineous kindreds
(7 Pakistani and 1 Moroccan), 5 of which had previously been described
by Ainsworth et al. (2001). All affected individuals from 5 families
were homozygous with respect to markers D2S410 and D2S1399. Genotyping
of additional microsatellite markers in family members of these 5
kindreds confirmed a region of homozygosity at chromosome 2q21.3.

MOLECULAR GENETICS

Aligianis et al. (2005) identified inactivating mutations in the
RAB3GAP1 gene (e.g., 602536.0001) in 5 kindreds with Warburg Micro
syndrome linked to chromosome 2q21.3, 2 of which had previously been
described by Ainsworth et al. (2001), but not in 3 unlinked kindreds.
Investigation of an additional 10 families with Warburg Micro syndrome
identified germline inactivating mutations in 7 families, including the
family in which Warburg Micro syndrome was first described (Warburg et
al., 1993) and 2 other families previously reported by Megarbane et al.
(1999) and Graham et al. (2004), respectively. Kindreds with or without
mutations in RAB3GAP1 were clinically indistinguishable.

Abdel-Salam et al. (2007) performed linkage analysis using markers
flanking the RAB3GAP1 and RAB3GAP2 genes in 2 unrelated Egyptian
patients with clinical features of Micro syndrome and found homozygosity
for all markers flanking RAB3GAP1 in a 2-year-old boy, in whom they
identified an R671X mutation (602536.0004) in the RAB3GAP1 gene. The
other patient, an 11-month-old girl with an affected older brother who
died at 2.5 years of age, showed no evidence of linkage to either gene.

In 7 patients with Warburg Micro syndrome from 5 families with Turkish,
Palestinian, Danish, and Guatemalan backgrounds, Morris-Rosendahl et al.
(2010) identified homozygosity for 5 different truncating RAB3GAP1
mutations, respectively (see, e.g., 602536.0006 and 602536.0007).

*FIELD* RF
1. Abdel-Salam, G. M. H.; Hassan, N. A.; Kayed, H. F.; Aligianis,
I. A.: Phenotypic variability in Micro syndrome: report of new cases. Genet.
Counsel. 18: 423-435, 2007.

2. Ainsworth, J. R.; Morton, J. E.; Good, P.; Woods, C. G.; George,
N. D. L.; Shield, J. P.; Bradbury, J.; Henderson, M. J.; Chhina, J.
: Micro syndrome in Muslim Pakistan children. Ophthalmology 108:
491-497, 2001.

3. Aligianis, I. A.; Johnson, C. A.; Gissen, P.; Chen, D.; Hampshire,
D.; Hoffmann, K.; Maina, E. N.; Morgan, N. V.; Tee, L.; Morton, J.;
Ainsworth, J. R.; Horn, D.; and 20 others: Mutations of the catalytic
subunit of RAB3GAP cause Warburg Micro syndrome. Nature Genet. 37:
221-223, 2005.

4. Balci, S.; Say, B.; Firat, T.: Corneal opacity, microphthalmia,
mental retardation, microcephaly and generalized muscular spasticity
associated with hyperglycinemia. Clin. Genet. 5: 36-39, 1974.

5. Derbent, M.; Agras, P. I.; Gedik, S.; Oto, S.; Alehan, F.; Saatci,
U.: Congenital cataract, microphthalmia, hypoplasia of corpus callosum
and hypogenitalism: report and review of Micro syndrome. Am. J. Med.
Genet. 128A: 232-234, 2004.

6. Graham, J. M., Jr.; Hennekam, R.; Dobyns, W. B.; Roeder, E.; Busch,
D.: MICRO syndrome: an entity distinct from COFS syndrome. Am. J.
Med. Genet. 128A: 235-245, 2004.

7. Megarbane, A.; Choueiri, R.; Bleik, J.; Mezzina, M.; Caillaud,
C.: Microcephaly, microphthalmia, congenital cataract, optic atrophy,
short stature, hypotonia, severe psychomotor retardation, and cerebral
malformations: a second family with Micro syndrome or a new syndrome? J.
Med. Genet. 36: 637-640, 1999.

8. Morris-Rosendahl, D. J.; Segel, R.; Born, A. P.; Conrad, C.; Loeys,
B.; Brooks, S. S.; Muller, L.; Zeschnigk, C.; Botti, C.; Rabinowitz,
R.; Uyanik, G.; Crocq, M.-A.; Kraus, U.; Degen, I.; Faes, F.: New
RAB3GAP1 mutations in patients with Warburg Micro syndrome from different
ethnic backgrounds and a possible founder effect in the Danish. Europ.
J. Hum. Genet. 18: 1100-1106, 2010.

9. Pinsky, L.; DiGeorge, A. M.; Harley, R. D.; Baird, H. W., III:
Microphthalmos, corneal opacity, mental retardation, and spastic cerebral
palsy: an oculocerebral syndrome. J. Pediat. 67: 387-398, 1965.

10. Rodriguez Criado, G.; Rufo, M.; Gomez de Terreros, I.: A second
family with Micro syndrome. Clin. Dysmorph. 8: 241-245, 1999.

11. Sjogren, T.; Larsson, T.: Microphthalmos and anophthalmos with
or without coincident oligophrenia: a clinical and genetic-statistical
study. Acta Psychiat. Neurol. Scand. 56 (suppl.): 1-103, 1949.

12. Warburg, M.; Sjo, O.; Fledelius, H. C.; Pedersen, S. A.: Autosomal
recessive microcephaly, microcornea, congenital cataract, mental retardation,
optic atrophy, and hypogenitalism: Micro syndrome. Am. J. Dis. Child. 147:
1309-1312, 1993.

13. Yuksel, A.; Yesil, G.; Aras, C.; Seven, M.: Warburg Micro syndrome
in a Turkish boy. Clin. Dysmorph. 16: 89-93, 2007.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature;
[Other];
Postnatal failure to thrive

HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Micrognathia;
[Ears];
Large ears;
[Eyes];
Microphthalmia;
Microcornea;
Congenital cataract;
Optic atrophy;
Ptosis;
Deep-set eyes

GENITOURINARY:
[External genitalia, male];
Hypogenitalism;
[Internal genitalia, male];
Cryptorchidism

SKELETAL:
Osteoporosis;
[Spine];
Kyphoscoliosis;
[Limbs];
Joint hypermobility (rare);
[Hands];
Joint hypermobility (rare);
[Feet];
Deformities of metatarsal bones (rare);
Overlapping toes (rare)

SKIN, NAILS, HAIR:
[Hair];
Facial hypertrichosis

NEUROLOGIC:
[Central nervous system];
Mental retardation;
Hypoplasia of the corpus callosum;
Agenesis of the corpus callosum;
Hypotonia;
Spastic diplegia;
Cerebral atrophy;
Cerebral malformations;
Hyperreflexia;
Cerebellar hypoplasia

MOLECULAR BASIS:
Caused by mutation in the RAB3 GTPase-activating protein gene (RAB3GAP,
602536.0001)

*FIELD* CN
Nara Sobreira - updated: 07/12/2010
Joanna S. Amberger - updated: 3/31/2005

*FIELD* CD
Ada Hamosh: 8/23/2001

*FIELD* ED
joanna: 07/12/2010
joanna: 12/12/2005
joanna: 3/31/2005
joanna: 8/24/2001
joanna: 8/23/2001
joanna: 12/15/1998

*FIELD* CN
Marla J. F. O'Neill - updated: 10/31/2011
Marla J. F. O'Neill - updated: 11/9/2010
Nara Sobreira - updated: 6/4/2009
Marla J. F. O'Neill - updated: 3/18/2008
Marla J. F. O'Neill - updated: 12/18/2006
Marla J. F. O'Neill - updated: 5/9/2006
Victor A. McKusick - updated: 3/9/2005
Marla J. F. O'Neill - updated: 9/28/2004
Michael J. Wright - updated: 10/27/1999

*FIELD* CD
Victor A. McKusick: 9/16/1994

*FIELD* ED
carol: 11/21/2012
terry: 1/13/2012
carol: 10/31/2011
carol: 9/14/2011
terry: 9/14/2011
carol: 9/12/2011
wwang: 11/17/2010
terry: 11/9/2010
terry: 5/28/2010
carol: 6/4/2009
terry: 6/4/2009
wwang: 3/19/2008
terry: 3/18/2008
carol: 12/18/2006
carol: 5/9/2006
terry: 5/9/2006
mgross: 3/11/2005
terry: 3/9/2005
carol: 9/28/2004
tkritzer: 9/28/2004
carol: 3/13/2003
carol: 8/23/2001
alopez: 10/27/1999
mimadm: 9/23/1995
carol: 9/16/1994

MIM 602536
*RECORD*
*FIELD* NO
602536
*FIELD* TI
*602536 RAB3 GTPase-ACTIVATING PROTEIN, CATALYTIC SUBUNIT; RAB3GAP1
;;RAB3GAP;;
RAB3GAP, 130-KD SUBUNIT;;
read moreRAB3GAP, CATALYTIC SUBUNIT;;
p130;;
WARBM1 GENE;;
KIAA0066
*FIELD* TX

DESCRIPTION

Members of the RAB3 protein family (see RAB3A; 179490) are implicated in
regulated exocytosis of neurotransmitters and hormones. RAB3GAP, which
is involved in regulation of RAB3 activity, is a heterodimeric complex
consisting a 130-kD catalytic subunit and a 150-kD noncatalytic subunit
(609275). RAB3GAP specifically converts active RAB3-GTP to the inactive
form RAB3-GDP (Aligianis et al., 2005).

CLONING

Fukui et al. (1997) isolated a protein from rat brain that showed GAP
activity for Rab3a. They used peptide sequences from this Rab3gap to
clone a corresponding cDNA from a human brain library. The human RAB3GAP
cDNA encodes a 981-amino acid polypeptide. Northern blot analysis showed
that RAB3GAP was ubiquitously expressed in human tissues as a 4.5-kb
mRNA.

GENE FUNCTION

By coimmunoprecipitation of rat brain synaptic soluble fractions, Nagano
et al. (1998) found a strong direct interaction between a 150-kD protein
(p150) and a 130-kD protein (p130) that showed GAP activity toward Rab3
family members. p150 did not show GAP activity, and the interaction
between p150 and p130 did not alter the activity of p130 or the
subcellular distribution of the 2 proteins.

GENE STRUCTURE

Aligianis et al. (2005) determined that the RAB3GAP1 gene contains 24
exons.

MAPPING

By genomic sequence analysis, Aligianis et al. (2005) mapped the
RAB3GAP1 gene to chromosome 2q21.3.

MOLECULAR GENETICS

Warburg Micro syndrome-1 (WARBM1; 600118) is characterized by ocular and
neurodevelopmental defects and hypothalamic hypogenitalism. Aligianis et
al. (2005) identified inactivating mutations in the RAB3GAP1 gene (e.g.,
602536.0001) in 5 consanguineous kindreds with Warburg Micro syndrome
linked to chromosome 2q21.3, but not in 3 unlinked kindreds.
Investigation of an additional 10 families identified germline
inactivating mutations in 7 families. The findings indicated that
RAB3GAP1 is essential for normal eye and brain development. Aligianis et
al. (2005) suggested that microgenitalia may result from hypothalamic
hypogonadotropism, and the ocular developmental defects and
neurodevelopmental abnormalities may be linked to abnormal
neurotransmitter vesicular transport and exocytosis.

In 7 patients with Warburg Micro syndrome-1 from 5 families with
Turkish, Palestinian, Danish, and Guatemalan backgrounds,
Morris-Rosendahl et al. (2010) identified homozygosity for 5 different
truncating RAB3GAP1 mutations, respectively (see, e.g., 602536.0006 and
602536.0007).

ANIMAL MODEL

Sakane et al. (2006) found that p130-deficient mice were viable and
fertile. Unlike Micro syndrome patients, they showed no ocular and
neurodevelopmental defects, and the layered structure of the cerebral
cortex and the hippocampus was no different from wildtype brains. In the
hippocampal CA1 and CA3 regions, Rab3a colocalized with synapsin I
(SYN1; 313440) at presynaptic terminals in both p130-deficient mice and
wildtype mice. Expression of p150 was severely attenuated in
p150-deficient mice, presumably due to its destabilization in the
absence of p130. Functionally, loss of p130 resulted in inhibition of
Ca(2+)-dependent glutamate release from cerebrocortical synaptosomes and
altered short-term plasticity in the hippocampal CA1 region. Sakane et
al. (2006) concluded that RAB3GAP regulates synaptic transmission and
plasticity by limiting the amount of GTP-bound RAB3A.

*FIELD* AV
.0001
WARBURG MICRO SYNDROME 1
RAB3GAP1, 1-BP DEL, 2801C

In 2 Pakistani kindreds with Warburg Micro syndrome-1 (600118),
Aligianis et al. (2005) identified a homozygous 1-bp deletion of C at
nucleotide 2801 in the last exon of the RAB3GAP1 gene. The mutation
resulted in a frameshift that added 38 amino acids to the C terminus of
the protein.

.0002
WARBURG MICRO SYNDROME 1
RAB3GAP1, IVS7AS, A-G, -2

Aligianis et al. (2005) identified a homozygous acceptor splice site
mutation in intron 7 of the RAB3GAP1 gene, an A-to-G transition at
position -2, in affected individuals of 3 apparently unrelated kindreds
with Warburg Micro syndrome-1 (600118), including the family in which
Warburg Micro syndrome was first described (Warburg et al., 1993). All 3
of these families (K5, K9, and K10) were of Pakistani origin, and
genotyping at 5 closely linked microsatellite markers was consistent
with a common haplotype, suggestive of a founder effect.

.0003
WARBURG MICRO SYNDROME 1
RAB3GAP1, IVS8DS, G-A, +1

In a Turkish family with Warburg Micro syndrome-1 (600118), Aligianis et
al. (2005) identified a homozygous donor splice site mutation in intron
8 of the RAB3GAP1 gene, a G-to-A transition at position +1. The mutation
resulted in skipping of exon 8 and, consequently, a frameshift.

Yuksel et al. (2007) identified homozygosity for the same mutation
(748+1G-A) in a 4-year-old Turkish boy with Warburg Micro syndrome.

.0004
WARBURG MICRO SYNDROME 1
RAB3GAP1, ARG671TER

In a consanguineous Lebanese family with a phenotype resembling that of
Warburg Micro syndrome-1 (600118), previously reported by Megarbane et
al. (1999), Aligianis et al. (2005) identified homozygosity for a
2011C-T transition in exon 18 of the RAB3GAP1 gene, resulting in an
arg671-to-ter (R671X) substitution.

In a 2-year-old Egyptian boy with features consistent with Micro
syndrome, Abdel-Salam et al. (2007) identified homozygosity for the
R671X mutation in the RAB3GAP1 gene.

.0005
WARBURG MICRO SYNDROME 1
RAB3GAP1, TRP578TER

In a consanguineous Mexican family with Warburg Micro syndrome-1
(600118), previously reported by Graham et al. (2004), Aligianis et al.
(2005) identified homozygosity for a 1734G-A transition in exon 17 of
the RAB3GAP1 gene, resulting in a trp578-to-ter (W578X) substitution.

.0006
WARBURG MICRO SYNDROME 1
RAB3GAP1, TYR470TER

In a female infant with Warburg Micro syndrome-1 (600118), born of
nonconsanguineous Danish parents, Morris-Rosendahl et al. (2010)
identified homozygosity for a 1410C-A transversion in exon 15 of the
RAB3GAP1 gene, predicted to result in a tyr470-to-ter (Y470X)
substitution. The unaffected parents were heterozygous for the mutation.
Analysis of 9 polymorphic markers flanking the RAB3GAP1 gene revealed a
homozygous haplotype in the patient that was shared by her unrelated
heterozygous parents, suggesting a possible founder effect for the
mutation in the Danish population.

.0007
WARBURG MICRO SYNDROME 1
RAB3GAP1, 7-BP DEL/6-BP INS, NT264

In a brother and sister with Warburg Micro syndrome-1 (600118), born of
distantly related Guatemalan parents, Morris-Rosendahl et al. (2010)
identified homozygosity for a 7-bp deletion/6-bp insertion
(264delAAAGGATinsTTATTA) in exon 4 of the RAB3GAP1 gene, resulting in a
frameshift and premature stop at codon 90. The unaffected parents were
heterozygous for the mutation.

*FIELD* RF
1. Abdel-Salam, G. M. H.; Hassan, N. A.; Kayed, H. F.; Aligianis,
I. A.: Phenotypic variability in Micro syndrome: report of new cases. Genet.
Counsel. 18: 423-435, 2007.

2. Aligianis, I. A.; Johnson, C. A.; Gissen, P.; Chen, D.; Hampshire,
D.; Hoffmann, K.; Maina, E. N.; Morgan, N. V.; Tee, L.; Morton, J.;
Ainsworth, J. R.; Horn, D.; and 20 others: Mutations of the catalytic
subunit of RAB3GAP cause Warburg Micro syndrome. Nature Genet. 37:
221-223, 2005.

3. Fukui, K.; Sasaki, T.; Imazumi, K.; Matsuura, Y.; Nakanishi, H.;
Takai, Y.: Isolation and characterization of a GTPase activating
protein specific for the Rab3 subfamily of small G proteins. J. Biol.
Chem. 272: 4655-4658, 1997.

4. Graham, J. M., Jr.; Hennekam, R.; Dobyns, W. B.; Roeder, E.; Busch,
D.: MICRO syndrome: an entity distinct from COFS syndrome. Am. J.
Med. Genet. 128A: 235-245, 2004.

5. Megarbane, A.; Choueiri, R.; Bleik, J.; Mezzina, M.; Caillaud,
C.: Microcephaly, microphthalmia, congenital cataract, optic atrophy,
short stature, hypotonia, severe psychomotor retardation, and cerebral
malformations: a second family with Micro syndrome or a new syndrome? J.
Med. Genet. 36: 637-640, 1999.

6. Morris-Rosendahl, D. J.; Segel, R.; Born, A. P.; Conrad, C.; Loeys,
B.; Brooks, S. S.; Muller, L.; Zeschnigk, C.; Botti, C.; Rabinowitz,
R.; Uyanik, G.; Crocq, M.-A.; Kraus, U.; Degen, I.; Faes, F.: New
RAB3GAP1 mutations in patients with Warburg Micro syndrome from different
ethnic backgrounds and a possible founder effect in the Danish. Europ.
J. Hum. Genet. 18: 1100-1106, 2010.

7. Nagano, F.; Sasaki, T.; Fukui, K.; Asakura, T.; Imazumi, K.; Takai,
Y.: Molecular cloning and characterization of the noncatalytic subunit
of the Rab3 subfamily-specific GTPase-activating protein. J. Biol.
Chem. 273: 24781-24785, 1998.

8. Sakane, A.; Manabe, S.; Ishizaki, H.; Tanaka-Okamoto, M.; Kiyokage,
E.; Toida, K.; Yoshida, T.; Miyoshi, J.; Kamiya, H.; Takai, Y.; Sasaki,
T.: Rab3 GTPase-activating protein regulates synaptic transmission
and plasticity through the inactivation of Rab3. Proc. Nat. Acad.
Sci. 103: 10029-10034, 2006.

9. Warburg, M.; Sjo, O.; Fledelius, H. C.; Pedersen, S. A.: Autosomal
recessive microcephaly, microcornea, congenital cataract, mental retardation,
optic atrophy, and hypogenitalism: Micro syndrome. Am. J. Dis. Child. 147:
1309-1312, 1993.

10. Yuksel, A.; Yesil, G.; Aras, C.; Seven, M.: Warburg Micro syndrome
in a Turkish boy. Clin. Dysmorph. 16: 89-93, 2007.

*FIELD* CN
Marla J. F. O'Neill - updated: 11/9/2010
Nara Sobreira - updated: 6/4/2009
Marla J. F. O'Neill - updated: 3/18/2008
Patricia A. Hartz - updated: 8/16/2006
Marla J. F. O'Neill - updated: 5/9/2006
Patricia A. Hartz - updated: 3/25/2005
Victor A. McKusick - updated: 3/9/2005

*FIELD* CD
Jennifer P. Macke: 4/20/1998

*FIELD* ED
carol: 09/12/2011
wwang: 11/17/2010
terry: 11/9/2010
carol: 6/4/2009
terry: 6/4/2009
wwang: 3/19/2008
terry: 3/18/2008
mgross: 8/25/2006
terry: 8/16/2006
carol: 5/9/2006
terry: 5/9/2006
alopez: 3/17/2006
mgross: 3/25/2005
mgross: 3/11/2005
terry: 3/9/2005
alopez: 6/3/1999
dholmes: 5/12/1998