RBCC Red Blood Cell Collection

GPHN (GPH, KIAA1385) [Confidence: low (only semi-automatic identification from reviews)]
Gephyrin; Molybdopterin adenylyltransferase; MPT adenylyltransferase; 2.7.7.75 (Domain G; Molybdopterin molybdenumtransferase; MPT Mo-transferase; 2.10.1.1; Domain E)

UniProt Q9NQX3
ID GEPH_HUMAN Reviewed; 736 AA.
AC Q9NQX3; Q9H4E9; Q9P2G2;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Gephyrin;
DE Includes:
DE RecName: Full=Molybdopterin adenylyltransferase;
DE Short=MPT adenylyltransferase;
DE EC=2.7.7.75;
DE AltName: Full=Domain G;
DE Includes:
DE RecName: Full=Molybdopterin molybdenumtransferase;
DE Short=MPT Mo-transferase;
DE EC=2.10.1.1;
DE AltName: Full=Domain E;
GN Name=GPHN; Synonyms=GPH, KIAA1385;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND DISEASE.
RX PubMed=11095995; DOI=10.1086/316941;
RA Reiss J., Gross-Hardt S., Christensen E., Schmidt P., Mendel R.R.,
RA Schwarz G.;
RT "A mutation in the gene for the neurotransmitter receptor-clustering
RT protein gephyrin causes a novel form of molybdenum cofactor
RT deficiency.";
RL Am. J. Hum. Genet. 68:208-213(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Kidney;
RX PubMed=11418245; DOI=10.1016/S0378-1119(01)00511-X;
RA David-Watine B.;
RT "The human gephyrin (GPHN) gene: structure, chromosome localization
RT and expression in non-neuronal cells.";
RL Gene 271:239-245(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI.
RT The complete sequences of 150 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-266, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [6]
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 [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188 AND SER-194, AND
RP MASS SPECTROMETRY.
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 [8]
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 [9]
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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188 AND SER-194, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 1-181, AND SUBUNIT.
RX PubMed=11554796; DOI=10.1006/jmbi.2001.4952;
RA Schwarz G., Schrader N., Mendel R.R., Hecht H.-J., Schindelin H.;
RT "Crystal structures of human gephyrin and plant Cnx1 G domains:
RT comparative analysis and functional implications.";
RL J. Mol. Biol. 312:405-418(2001).
RN [12]
RP VARIANT TYR-10, AND CHARACTERIZATION OF VARIANT TYR-10.
RX PubMed=12684523; DOI=10.1074/jbc.M301070200;
RA Rees M.I., Harvey K., Ward H., White J.H., Evans L., Duguid I.C.,
RA Hsu C.-C., Coleman S.L., Miller J., Baer K., Waldvogel H.J.,
RA Gibbon F., Smart T.G., Owen M.J., Harvey R.J., Snell R.G.;
RT "Isoform heterogeneity of the human gephyrin gene (GPHN), binding
RT domains to the glycine receptor, and mutation analysis in
RT hyperekplexia.";
RL J. Biol. Chem. 278:24688-24696(2003).
CC -!- FUNCTION: Microtubule-associated protein involved in membrane
CC protein-cytoskeleton interactions. It is thought to anchor the
CC inhibitory glycine receptor (GLYR) to subsynaptic microtubules (By
CC similarity). Catalyzes two steps in the biosynthesis of the
CC molybdenum cofactor. In the first step, molybdopterin is
CC adenylated. Subsequently, molybdate is inserted into adenylated
CC molybdopterin and AMP is released.
CC -!- CATALYTIC ACTIVITY: ATP + molybdopterin = diphosphate + adenylyl-
CC molybdopterin.
CC -!- CATALYTIC ACTIVITY: Adenylyl-molybdopterin + molybdate =
CC molybdenum cofactor + AMP.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- ENZYME REGULATION: Inhibited by copper and tungsten (By
CC similarity).
CC -!- PATHWAY: Cofactor biosynthesis; molybdopterin biosynthesis.
CC -!- SUBUNIT: Homotrimer. Interacts with GABARAP (By similarity).
CC Interacts with SRGAP2 (via SH3 domain) (By similarity).
CC -!- SUBCELLULAR LOCATION: Cell junction, synapse (By similarity). Cell
CC junction, synapse, postsynaptic cell membrane; Peripheral membrane
CC protein; Cytoplasmic side (By similarity). Cytoplasm, cytoskeleton
CC (By similarity). Note=Cytoplasmic face of glycinergic postsynaptic
CC membranes (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9NQX3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NQX3-2; Sequence=VSP_021769;
CC -!- DISEASE: Molybdenum cofactor deficiency type C (MOCOD type C)
CC [MIM:252150]: Autosomal recessive disease which leads to the
CC pleiotropic loss of all molybdoenzyme activities and is
CC characterized by severe neurological damage, neonatal seizures and
CC early childhood death. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the MoaB/Mog
CC family.
CC -!- SIMILARITY: In the C-terminal section; belongs to the MoeA family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA92623.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/GPHNID317.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GPHN";
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DR EMBL; AF272663; AAF81785.1; -; mRNA.
DR EMBL; AJ272343; CAC10537.1; -; mRNA.
DR EMBL; AB037806; BAA92623.1; ALT_INIT; mRNA.
DR EMBL; BC030016; AAH30016.1; -; mRNA.
DR RefSeq; NP_001019389.1; NM_001024218.1.
DR RefSeq; NP_065857.1; NM_020806.4.
DR UniGene; Hs.208765; -.
DR PDB; 1JLJ; X-ray; 1.60 A; A/B/C=1-181.
DR PDBsum; 1JLJ; -.
DR ProteinModelPortal; Q9NQX3; -.
DR SMR; Q9NQX3; 13-181, 318-736.
DR IntAct; Q9NQX3; 8.
DR MINT; MINT-139581; -.
DR STRING; 9606.ENSP00000303019; -.
DR PhosphoSite; Q9NQX3; -.
DR DMDM; 13431554; -.
DR PaxDb; Q9NQX3; -.
DR PRIDE; Q9NQX3; -.
DR DNASU; 10243; -.
DR Ensembl; ENST00000315266; ENSP00000312771; ENSG00000171723.
DR Ensembl; ENST00000478722; ENSP00000417901; ENSG00000171723.
DR GeneID; 10243; -.
DR KEGG; hsa:10243; -.
DR UCSC; uc001xiy.3; human.
DR CTD; 10243; -.
DR GeneCards; GC14P066974; -.
DR HGNC; HGNC:15465; GPHN.
DR HPA; CAB004419; -.
DR HPA; HPA003116; -.
DR HPA; HPA024694; -.
DR MIM; 252150; phenotype.
DR MIM; 603930; gene.
DR neXtProt; NX_Q9NQX3; -.
DR Orphanet; 3197; Hereditary hyperekplexia.
DR Orphanet; 308400; Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C.
DR PharmGKB; PA28840; -.
DR eggNOG; COG0303; -.
DR HOGENOM; HOG000280651; -.
DR HOVERGEN; HBG005828; -.
DR KO; K15376; -.
DR OrthoDB; EOG70087N; -.
DR BioCyc; MetaCyc:ENSG00000171723-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR UniPathway; UPA00344; -.
DR ChiTaRS; GPHN; human.
DR EvolutionaryTrace; Q9NQX3; -.
DR GeneWiki; GPHN; -.
DR GenomeRNAi; 10243; -.
DR NextBio; 38806; -.
DR PRO; PR:Q9NQX3; -.
DR ArrayExpress; Q9NQX3; -.
DR Bgee; Q9NQX3; -.
DR CleanEx; HS_GPHN; -.
DR Genevestigator; Q9NQX3; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016740; F:transferase activity; TAS:Reactome.
DR GO; GO:0007529; P:establishment of synaptic specificity at neuromuscular junction; IEA:Ensembl.
DR GO; GO:0006777; P:Mo-molybdopterin cofactor biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0032324; P:molybdopterin cofactor biosynthetic process; TAS:Reactome.
DR GO; GO:0006767; P:water-soluble vitamin metabolic process; TAS:Reactome.
DR Gene3D; 2.40.340.10; -; 1.
DR Gene3D; 3.40.980.10; -; 2.
DR InterPro; IPR020817; Mo_cofactor_synthesis.
DR InterPro; IPR008284; MoCF_biosynth_CS.
DR InterPro; IPR005111; MoeA_C_domain_IV.
DR InterPro; IPR005110; MoeA_linker/N.
DR InterPro; IPR001453; Mopterin-bd_dom.
DR Pfam; PF00994; MoCF_biosynth; 2.
DR Pfam; PF03454; MoeA_C; 1.
DR Pfam; PF03453; MoeA_N; 1.
DR SMART; SM00852; MoCF_biosynth; 2.
DR SUPFAM; SSF53218; SSF53218; 2.
DR SUPFAM; SSF63867; SSF63867; 1.
DR SUPFAM; SSF63882; SSF63882; 1.
DR TIGRFAMs; TIGR00177; molyb_syn; 2.
DR PROSITE; PS01078; MOCF_BIOSYNTHESIS_1; 1.
DR PROSITE; PS01079; MOCF_BIOSYNTHESIS_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell junction;
KW Cell membrane; Complete proteome; Cytoplasm; Cytoskeleton; Magnesium;
KW Membrane; Metal-binding; Molybdenum; Molybdenum cofactor biosynthesis;
KW Multifunctional enzyme; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Postsynaptic cell membrane; Reference proteome; Synapse;
KW Transferase.
FT CHAIN 1 736 Gephyrin.
FT /FTId=PRO_0000170964.
FT REGION 14 166 MPT Mo-transferase.
FT REGION 140 316 Interaction with GABARAP (By similarity).
FT REGION 326 736 MPT adenylyltransferase.
FT MOD_RES 188 188 Phosphoserine.
FT MOD_RES 194 194 Phosphoserine.
FT MOD_RES 266 266 Phosphothreonine.
FT MOD_RES 305 305 Phosphoserine (By similarity).
FT VAR_SEQ 243 243 K -> KKHPFYTSPAVVMAHGEQPIPGLINYSHHSTDER
FT (in isoform 2).
FT /FTId=VSP_021769.
FT VARIANT 10 10 N -> Y (found in a patient with
FT hyperekplexia; unknown pathological
FT significance; does not affect the
FT structural lattices formed by gephyrin;
FT dbSNP:rs121908539).
FT /FTId=VAR_044162.
FT STRAND 16 22
FT HELIX 24 27
FT HELIX 34 44
FT TURN 46 49
FT STRAND 52 59
FT HELIX 63 75
FT STRAND 80 86
FT STRAND 89 91
FT HELIX 96 103
FT STRAND 105 107
FT HELIX 109 122
FT HELIX 124 128
FT STRAND 133 136
FT STRAND 139 144
FT HELIX 148 158
FT HELIX 159 161
FT HELIX 162 169
FT HELIX 175 178
SQ SEQUENCE 736 AA; 79748 MW; E2BDA3AD3AB962C0 CRC64;
MATEGMILTN HDHQIRVGVL TVSDSCFRNL AEDRSGINLK DLVQDPSLLG GTISAYKIVP
DEIEEIKETL IDWCDEKELN LILTTGGTGF APRDVTPEAT KEVIEREAPG MALAMLMGSL
NVTPLGMLSR PVCGIRGKTL IINLPGSKKG SQECFQFILP ALPHAIDLLR DAIVKVKEVH
DELEDLPSPP PPLSPPPTTS PHKQTEDKGV QCEEEEEEKK DSGVASTEDS SSSHITAAAI
AAKIPDSIIS RGVQVLPRDT ASLSTTPSES PRAQATSRLS TASCPTPKVQ SRCSSKENIL
RASHSAVDIT KVARRHRMSP FPLTSMDKAF ITVLEMTPVL GTEIINYRDG MGRVLAQDVY
AKDNLPPFPA SVKDGYAVRA ADGPGDRFII GESQAGEQPT QTVMPGQVMR VTTGAPIPCG
ADAVVQVEDT ELIRESDDGT EELEVRILVQ ARPGQDIRPI GHDIKRGECV LAKGTHMGPS
EIGLLATVGV TEVEVNKFPV VAVMSTGNEL LNPEDDLLPG KIRDSNRSTL LATIQEHGYP
TINLGIVGDN PDDLLNALNE GISRADVIIT SGGVSMGEKD YLKQVLDIDL HAQIHFGRVF
MKPGLPTTFA TLDIDGVRKI IFALPGNPVS AVVTCNLFVV PALRKMQGIL DPRPTIIKAR
LSCDVKLDPR PEYHRCILTW HHQEPLPWAQ STGNQMSSRL MSMRSANGLL MLPPKTEQYV
ELHKGEVVDV MVIGRL
//

MIM 252150
*RECORD*
*FIELD* NO
252150
*FIELD* TI
#252150 MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A; MOCODA
;;SULFITE OXIDASE, XANTHINE DEHYDROGENASE, AND ALDEHYDE OXIDASE, COMBINED
read moreDEFICIENCY OF
*FIELD* TX
A number sign (#) is used with this entry because molybdenum cofactor
deficiency of complementation group A (MOCODA) is caused by homozygous
or compound heterozygous mutation in the MOCS1 gene (603707) on
chromosome 6p21.

DESCRIPTION

Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive
metabolic disorder characterized by onset in infancy of poor feeding,
intractable seizures, and severe psychomotor retardation. Characteristic
biochemical abnormalities include decreased serum uric acid and
increased urine sulfite levels due to the combined enzymatic deficiency
of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX;
606887), both of which use molybdenum as a cofactor. Most affected
individuals die in early childhood (summary by Reiss, 2000; Reiss et
al., 2011).

- Genetic Heterogeneity of Molybdenum Cofactor Deficiency

See also MOCOD, complementation group B (MOCODB; 252160), caused by
mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD,
complementation group C (MOCODC; 615501), caused by mutation in the GPHN
gene (603930) on chromosome 14q24.

CLINICAL FEATURES

Duran et al. (1978) reported a female infant with a combination of
sulfite oxidase deficiency (272300) and xanthine oxidase deficiency
(278300). She presented at age 10 days with poor feeding, tonic-clonic
seizures, EEG abnormalities, and dysmorphic features, including frontal
bossing, asymmetry of the skull, and subtle medio-facial dysplasia. She
also had nystagmus, enophthalmos, and dislocated lenses. Laboratory
studies showed low serum uric acid, and urinary analysis showed
increased excretion of xanthine, hypoxanthine, S-sulfocysteine, and
taurine. At age 14 months, she was noted to have excretion of xanthine
stones. At age 2 years, she had poor head control, hypertonia, no
reaction to light, and essentially no psychomotor development. Xanthine
oxidase activity was demonstrated to be absent in patient cells, but
sulfite oxidase activity was difficult to determine. However, the
excretion of sulfur-containing metabolites was consistent with decreased
sulfite oxidase activity. Serum molybdenum concentration was normal.
Johnson et al. (1980) reported further studies on the patient reported
by Duran et al. (1978), who was bedridden and had not achieved any
milestones by age 3 years. Hepatic tissue from the patient showed
deficient activities of both sulfite oxidase and xanthine dehydrogenase,
secondary to deficient synthesis of the molybdenum cofactor. Molybdenum
was absent in the liver sample despite normal serum levels of the metal;
however, the active molybdenum cofactor was not detectable in the liver.
The clinical features were attributed mainly to the deficiency of
sulfite oxidase; urinary xanthine stones were presumably the only
manifestation of the xanthine oxidase deficiency. There was also
indirect biochemical evidence of aldehyde oxidase (AOX1; 602841)
deficiency. Johnson et al. (1980) concluded that the patient had a
primary defect in an essential step of the biosynthesis of the active
molybdenum cofactor.

Beemer (1981) identified this disorder in a second patient, a male
newborn, whose parents were born in the same region of Holland as the
parents of the first patient, with at least 2 links between the
pedigrees. By 1983, according to Wadman et al. (1983), there were more
cases of sulfite oxidase deficiency due to a defect in the molybdenum
cofactor than cases of isolated sulfite oxidase deficiency. Convulsions,
feeding difficulties, mental retardation, and lens dislocation occurred
in both the isolated and the combined forms. In the combined form,
abnormal muscle tone, myoclonic spasms, and an abnormal physiognomy had
also been reported.

Endres et al. (1988) reported a newborn infant with seizures and spastic
tetraparesis at the age of 1 week who excreted excessive amounts of
sulfite, taurine, S-sulfocysteine and thiosulfate, characteristic of
sulfite oxidase deficiency. In addition, increased renal excretion of
xanthine and hypoxanthine combined with a low serum and urinary uric
acid was consistent with xanthine dehydrogenase deficiency. Both
deficiencies were established at the enzyme level. Attempts at treatment
were unsuccessful. The patient developed a severe neurologic syndrome,
brain atrophy, and lens dislocation, and died at the age of 22 months.

Slot et al. (1993) reported 2 unrelated patients with MOCOD who
presented with neonatal convulsions. The parents in one case were second
cousins. One infant died at the age of 10 days and was found to have
severe loss of neocortical neurons, predominantly affecting the deeper
layers, well-established gliosis of the white matter, and areas of
cystic lysis in the white matter. In the case of the second infant,
death occurred at the age of about 1 year. Postmortem examination, like
clinical examination, disclosed no lens luxation.

Parini et al. (1997) described a patient with molybdenum cofactor
deficiency in which lens dislocation developed late (at the age of 8
years) and was preceded by bilateral spherophakia. The authors
hypothesized that the cause of spherophakia in this disorder is an
abnormal relaxation of the zonular fibers, which eventually causes lens
dislocation.

Patients with MOCOD have recognizable dysmorphic facial features,
including long face with puffy cheeks, widely spaced eyes, elongated
palpebral fissures, thick lips, long philtrum, and small nose. Some
patients develop progressive microcephaly, whereas others have
macrocephaly secondary to hydrocephalus. Neuropathologic findings
include brain atrophy, neuronal loss, astrocytic gliosis, cystic changes
in the subcortical white matter, thin corpus callosum, enlarged
ventricles, and demyelination (summary by Johnson and Duran, 2001).

BIOCHEMICAL FEATURES

Johnson and Rajagopalan (1982) showed that urothione, a
sulfur-containing pterin, is the normal metabolic degradation product of
the molybdenum cofactor that is deficient in this disorder. Roesel et
al. (1986) found no detectable urinary urothione in a patient with
combined xanthine and sulfite oxidase deficiency.

From studies of cocultured fibroblasts from affected individuals,
Johnson et al. (1989) identified 2 complementation groups, A and B.
Coculture of group A and group B cells, without heterokaryon formation,
led to the appearance of active sulfite oxidase. Use of conditioned
media indicated that a relatively stable form of diffusible precursor
produced by group B cells could be used to repair sulfite oxidase in
group A recipient cells. Although the extremely low level of precursor
produced by group B cells precluded its direct characterization, studies
with a heterologous in vitro reconstitution system suggested that the
precursor that accumulates in group B cells is the same as a
molybdopterin precursor identified in a molybdopterin mutant of
Neurospora crassa, and that a converting enzyme is present in group A
cells which catalyzes an activation reaction analogous to that of a
converting enzyme identified in a molybdopterin mutant of E. coli.

INHERITANCE

The transmission pattern of molybdenum cofactor deficiency is consistent
with autosomal recessive inheritance (summary by Reiss, 2000).

DIAGNOSIS

Wadman et al. (1983) called attention to a very simple screening test
for urinary sulfite, which was originally developed for the
semiquantitative determination of sulfite in wine and fruit juices and
is available as a 'strip test.' Aukett et al. (1988) described a patient
presenting with seizures at age 4 weeks in whom the stick sulfite test,
by 2 techniques, was negative. They suggested that low serum urate may
be a better pointer to the diagnosis than the sulfite test.

Coskun et al. (1998) presented a case of MOCOD and stressed the value of
serum uric acid concentration in reaching the diagnosis. A very low
serum uric acid level reflects the deficiency of xanthine dehydrogenase,
one of the enzymes whose function is affected in this disorder.

- Prenatal Diagnosis

Gray et al. (1990) described prenatal diagnosis by demonstrating sulfite
oxidase deficiency in uncultured chorionic villus material.

Reiss et al. (1999) pointed out that since 1983 the prenatal diagnosis
of molybdenum cofactor deficiency had been made by measurement of
sulfite oxidase activity, but no enzymatic carrier diagnosis was
possible. With the cloning of the MOCS1 gene, it was possible for Reiss
et al. (1999) to perform enzymatic and molecular genetic analysis in
parallel after chorionic villus sampling in a Danish family. The sulfite
oxidase activity in uncultured CVS material was found to be normal. A
MOCS1 splice site mutation (603707.0004), found to be homozygous in the
proband, was found to be heterozygous in cultured chorionic cells. This
confirmed that the fetus was not affected, since heterozygous carriers
of the molybdenum cofactor deficiency do not display any symptoms.

MAPPING

By use of homozygosity mapping in 2 unrelated consanguineous kindreds of
Israeli Arab origin, Shalata et al. (1998) demonstrated linkage of
MOCODA to an 8-cM region on chromosome 6p21.3, between markers D6S1641
and D6S1672. Linkage analysis generated the highest combined lod score,
3.6, at a recombination fraction of 0.0, with marker D6S1575. In 1
extensive kindred, 11 homozygotes in 9 sibships related as cousins were
reported. The first affected member of this family had been reported by
Van Gennip et al. (1994). In a second kindred, 2 sibs were homozygous.
An immediate benefit of the mapping effort was the ability to perform
prenatal diagnosis and carrier detection by use of microsatellite
markers.

MOLECULAR GENETICS

In 2 unrelated patients with molybdenum cofactor deficiency of
complementation group A, Reiss et al. (1998) identified 2 different
homozygous truncating mutations in the MOCS1 gene (603707.0001 and
603707.0002); one mutation occurred in the MOCS1A transcript and the
other occurred in the MOCS1B transcript. These findings indicated the
existence of a eukaryotic mRNA which, as a single and uniform
transcript, guides the synthesis of 2 different enzymatic polypeptides
with disease-causing potential. Thus the MOCS1 gene is bicistronic.

In an initial cohort of 24 patients with molybdenum cofactor deficiency,
Reiss et al. (1998) identified 13 different mutations on 34 of the 48
chromosomes, giving a mutation detection rate of 70%. Five mutations
were observed in more than 1 patient and together accounted for
two-thirds of detected mutations. All patients with identified mutations
were either homozygous or compound heterozygous for mutations in either
of the 2 open reading frames corresponding to MOCS1A and MOCS1B,
respectively.

Reiss (2000) reviewed the genetics of molybdenum cofactor deficiency.
Both MOCS1 and MOCS2 have an unusual bicistronic architecture, have
identical very low expression profiles, and show extremely conserved
C-terminal ends in their 5-prime open reading frames. MOCS1 mutations
are responsible for two-thirds of cases. Reiss (2000) pointed out that
all described MOCS1 and MOCS2 mutations affect one or several highly
conserved motifs. No missense mutations of a less conserved residue were
identified. This mirrors the absence of mild or partial forms of MoCo
deficiency and supports the hypothesis of a qualitative 'yes or no'
mechanism rather than quantitative kinetics for MoCo function, i.e.,
this function is either completely abolished or sufficient for a normal
phenotype. The minimal expression of the MOCS genes concurs with this
theory and would predict a low level of transfected or expressing cells
that would be adequate for somatic gene therapy. Furthermore,
precursor-producing cells seem to be capable of feeding their
precursor-deficient neighbor cells (Johnson et al., 1989).

Reiss and Johnson (2003) collected a total of 32 different
disease-causing mutations in the MOCS1, MOCS2, or GPHN genes, including
several common to more than 1 family, that had been identified in
molybdenum cofactor-deficient patients and their relatives.

NOMENCLATURE

The mutations of MOCS1 causing molybdenum cofactor deficiency occur in
either the MOCS1A or MOCS1B isoforms, and similarly the mutations in
MOCS2 can occur in either the MOCS2A or MOSC2B isoforms. The form of
molybdenum cofactor deficiency caused by mutation in MOCS1 is called
here complementation group A (not type A); molybdenum cofactor
deficiency due to mutation in MOCS2 is referred to as complementation
group B; and molybdenum cofactor deficiency due to mutation in the GPHN
gene is referred to as complementation group C.

ANIMAL MODEL

Lee et al. (2002) constructed a transgenic mouse model of molybdenum
cofactor deficiency in which the MOCS1 gene was disrupted by homologous
recombination with a targeting vector. As in humans, heterozygous mice
displayed no symptoms, but homozygous animals died between days 1 and 11
after birth. Biochemical analysis of these animals showed that
molybdopterin and active cofactor were undetectable. The animals did not
possess any sulfite oxidase or xanthine dehydrogenase activity. No organ
abnormalities were observed and the synaptic localization of inhibitory
receptors, which was found to be disturbed in molybdenum
cofactor-deficient mice with a Geph mutation, appeared normal.

Schwarz et al. (2004) described the isolation of a pterin intermediate
from bacteria that was successfully used for the therapy of molybdenum
cofactor deficiency in a mouse model. An intermediate of this pathway,
designated 'precursor Z,' is more stable than the cofactor itself and
has an identical structure in all phyla. Schwarz et al. (2004)
overproduced precursor Z in E. coli and injected purified precursor
Z-deficient knockout mice, which displayed a phenotype resembling the
human deficiency state. Precursor Z-substituted mice reached adulthood
and fertility. Biochemical analyses further suggested that the described
treatment may lead to the alleviation of most symptoms associated with
human molybdenum cofactor deficiency.

The mouse model of MoCo deficiency type A (Lee et al., 2002; Schwarz et
al., 2004) showed the biochemical characteristics of sulfite and
xanthine intoxication and a failure to survive more than 2 weeks after
birth. Kugler et al. (2007) constructed an expression cassette for the
gene MOCS1 which, by alternative splicing, facilitates the expression of
the proteins MOCS1A and MOCS1B, both of which are necessary for the
formation of a first intermediate, cyclic pyranopterin monophosphate
(cPMP), within the biosynthetic pathway leading to active MoCo. A
recombinant adeno-associated virus (AAV) vector was used to express the
artificial MOCS1 minigene in an attempt to cure the lethal
MOCS1-deficient phenotype. The vector was used to transduce
Mocs1-deficient mice at both 1 and 4 days after birth or, after a
pretreatment with purified cPMP, at 40 days after birth. They found that
all deficient animals injected with control AAV-enhanced green
fluorescent protein vector died approximately 8 days after birth or
after withdrawal of cPMP supplementation, whereas AAV-MOCS1-transduced
animals showed significantly increased longevity. A single intrahepatic
injection of AAV-MOCS1 resulted in fertile adult animals without any
pathologic phenotypes.

*FIELD* SA
Beemer and Delleman (1980)
*FIELD* RF
1. Aukett, A.; Bennett, M. J.; Hosking, G. P.: Molybdenum cofactor
deficiency: an easily missed inborn error of metabolism. Dev. Med.
Child Neurol. 30: 531-535, 1988.

2. Beemer, F. A.: Personal Communication. Utrecht, The Netherlands
1/15/1981.

3. Beemer, F. A.; Delleman, J. W.: Combined deficiency of xanthine
oxidase and sulfite oxidase: ophthalmological findings in a 3-week-old
girl. Metab. Pediat. Ophthal. 4: 49-52, 1980.

4. Coskun, T.; Yetuk, M.; Yurdakok, M.; Tekinalp, G.: Blood uric
acid as a pointer to the diagnosis of molybdenum cofactor deficiency.
(Letter) Acta Pediat. 87: 714-715, 1998.

5. Duran, M.; Beemer, F. A.; v. d. Heiden, C.; Korteland, J.; de Bree,
P. K.; Brink, M.; Wadman, S. K.: Combined deficiency of xanthine
oxidase and sulphite oxidase: a defect of molybdenum metabolism or
transport? J. Inherit. Metab. Dis. 1: 175-178, 1978.

6. Endres, W.; Shin, Y. S.; Gunther, R.; Ibel, H.; Duran, M.; Wadman,
S. K.: Report on a new patient with combined deficiencies of sulphite
oxidase and xanthine dehydrogenase due to molybdenum cofactor deficiency. Europ.
J. Pediat. 148: 246-249, 1988.

7. Gray, R. G. F.; Green, A.; Basu, S. N.; Constantine, G.; Condie,
R. G.; Dorche, C.; Vianey-Liaud, C.; Desjacques, P.: Antenatal diagnosis
of molybdenum cofactor deficiency. Am. J. Obstet. Gynec. 163: 1203-1204,
1990.

8. Johnson, J. L.; Duran, M.: Molybdenum cofactor deficiency and
isolated sulfite oxidase deficiency.In: Scriver, C. R.; Beaudet, A.
L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases
of Inherited Disease. Vol. II. New York: McGraw-Hill (8th ed.)
: 2001. Pp. 3163-3177.

9. Johnson, J. L.; Rajagopalan, K. V.: Structural and metabolic relationship
between the molybdenum cofactor and urothione. Proc. Nat. Acad. Sci. 79:
6856-6860, 1982.

10. Johnson, J. L.; Waud, W. R.; Rajagopalan, K. V.; Duran, M.; Beemer,
F. A.; Wadman, S. K.: Inborn errors of molybdenum metabolism: combined
deficiencies of sulfite oxidase and xanthine dehydrogenase in a patient
lacking the molybdenum cofactor. Proc. Nat. Acad. Sci. 77: 3715-3719,
1980.

11. Johnson, J. L.; Wuebbens, M. M.; Mandell, R.; Shih, V. E.: Molybdenum
cofactor biosynthesis in humans: identification of two complementation
groups of cofactor-deficient patients and preliminary characterization
of a diffusible molybdopterin precursor. J. Clin. Invest. 83: 897-903,
1989.

12. Kugler, S.; Hahnewald, R.; Garrido, M.; Reiss, J.: Long-term
rescue of a lethal inherited disease by adeno-associated virus-mediated
gene transfer in a mouse model of molybdenum-cofactor deficiency. Am.
J. Hum. Genet. 80: 291-297, 2007.

13. Lee, H.-J.; Adham, I. M.; Schwarz, G.; Kneussel, M.; Sass, J.
O.; Engel, W.; Reiss, J.: Molybdenum cofactor-deficient mice resemble
the phenotype of human patients. Hum. Molec. Genet. 11: 3309-3317,
2002.

14. Parini, R.; Briscioli, V.; Caruso, U.; Dorche, C.; Fortuna, R.;
Minniti, G.; Selicorni, A.; Vismara, E.; Mancini, G.: Spherophakia
associated with molybdenum cofactor deficiency. Am. J. Med. Genet. 73:
272-275, 1997.

15. Reiss, J.: Genetics of molybdenum cofactor deficiency. Hum.
Genet. 106: 157-163, 2000.

16. Reiss, J.; Christensen, E.; Dorche, C.: Molybdenum cofactor deficiency:
first prenatal genetic analysis. Prenatal Diag. 19: 386-388, 1999.

17. Reiss, J.; Christensen, E.; Kurlemann, G.; Zabot, M.-T.; Dorche,
C.: Genomic structure and mutational spectrum of the bicistronic
MOCS1 gene defective in molybdenum cofactor deficiency type A. Hum.
Genet. 103: 639-644, 1998.

18. Reiss, J.; Cohen, N.; Dorche, C.; Mandel, H.; Mendel, R. R.; Stallmeyer,
B.; Zabot, M.-T.; Dierks, T.: Mutations in a polycistronic nuclear
gene associated with molybdenum cofactor deficiency. Nature Genet. 20:
51-53, 1998.

19. Reiss, J.; Johnson, J. L.: Mutations in the molybdenum cofactor
biosynthetic genes MOCS1, MOCS2, and GEPH. Hum. Mutat. 21: 569-576,
2003.

20. Reiss, J.; Lenz, U.; Aquaviva-Bourdain, C.; Joriot-Chekaf, S.;
Mention-Mulliez, K.; Holder-Espinasse, M.: A GPHN point mutation
leading to molybdenum cofactor deficiency. (Letter) Clin. Genet. 80:
598-599, 2011.

21. Roesel, R. A.; Bowyer, F.; Blankenship, P. R.; Hommes, F. A.:
Combined xanthine and sulphite oxidase defect due to a deficiency
of molybdenum cofactor. J. Inherit. Metab. Dis. 9: 343-347, 1986.

22. Schwarz, G.; Santamaria-Araujo, J. A.; Wolf, S.; Lee, H.-J.; Adham,
I. M.; Grone, H.-J.; Schwegler, H.; Sass, J. O.; Otte, T.; Hanzelmann,
P.; Mendel, R. R.; Engel, W.; Reiss, J.: Rescue of lethal molybdenum
cofactor deficiency by a biosynthetic precursor from Escherichia coli. Hum.
Molec. Genet. 13: 1249-1255, 2004.

23. Shalata, A.; Mandel, H.; Reiss, J.; Szargel, R.; Cohen-Akenine,
A.; Dorche, C.; Zabot, M.-T.; Van Gennip, A.; Abeling, N.; Berant,
M.; Cohen, N.: Localization of a gene for molybdenum cofactor deficiency,
on the short arm of chromosome 6, by homozygosity mapping. Am. J.
Hum. Genet. 63: 148-154, 1998.

24. Slot, H. M. J.; Overweg-Plandsoen, W. C. G.; Bakker, H. D.; Abeling,
N. G. G. M.; Tamminga, P.; Barth, P. G.; Van Gennip, A. H.: Molybdenum-cofactor
deficiency: an easily missed cause of neonatal convulsions. Neuropediatrics 24:
139-142, 1993.

25. Van Gennip, A. H.; Mandel, H.; Stroomer, L. E.; van Cruchten,
A. G.: Effect of allopurinol on the xanthinuria in a patient with
molybdenum cofactor deficiency. Adv. Exp. Med. Biol. 370: 375-378,
1994.

26. Wadman, S. K.; Cats, B. P.; de Bree, P. K.: Sulfite oxidase deficiency
and the detection of urinary sulfite. (Letter) Europ. J. Pediat. 141:
62-63, 1983.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Poor growth

HEAD AND NECK:
[Head];
Frontal bossing;
Microcephaly;
Macrocephaly;
[Face];
Long face;
Puffy cheeks;
Long philtrum;
[Eyes];
Dislocated lenses;
Spherophakia;
Nystagmus;
Elongated palpebral fissures;
Widely spaced eyes;
[Nose];
Small nose;
[Mouth];
Thick lips

ABDOMEN:
[Gastrointestinal];
Poor feeding

SKELETAL:
[Skull];
Asymmetric skull

MUSCLE, SOFT TISSUE:
Myoclonic spasms

NEUROLOGIC:
[Central nervous system];
Absent or delayed psychomotor development, severe;
Seizures, intractable;
Opisthotonos;
Hypertonicity;
Spastic quadriplegia;
Cerebral atrophy;
Thinning of the corpus callosum;
Gliosis;
Demyelination;
Axonal loss;
Cystic lysis of the deep white matter;
Enlarged ventricles

LABORATORY ABNORMALITIES:
Hypouricemia;
Increased urinary xanthine;
Increased urinary hypoxanthine;
Increased urinary S-sulfocysteine;
Increased urinary taurine;
Xanthine stones;
Decreased xanthine dehydrogenase activity;
Decreased sulfite oxidase activity;
Molybdenum cofactor deficiency

MISCELLANEOUS:
Onset at birth or in early infancy;
Progressive disorder;
Most affected patients die in childhood

MOLECULAR BASIS:
Caused by mutation in the molybdenum cofactor synthesis gene 1 (MOCS1,
603707.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 10/30/2013

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

*FIELD* ED
joanna: 12/09/2013
ckniffin: 10/30/2013
joanna: 11/12/1997

*FIELD* CN
Cassandra L. Kniffin - updated: 10/30/2013
Victor A. McKusick - updated: 1/19/2007
George E. Tiller - updated: 9/7/2006
Marla J. F. O'Neill - updated: 11/16/2005
George E. Tiller - updated: 9/10/2004
Victor A. McKusick - updated: 7/11/2003
Sonja A. Rasmussen - updated: 12/7/2001
Victor A. McKusick - updated: 1/23/2001
Victor A. McKusick - updated: 3/8/2000
Rebekah S. Rasooly - updated: 6/22/1999
Victor A. McKusick - updated: 6/9/1999
Victor A. McKusick - updated: 4/8/1999
Victor A. McKusick - updated: 3/22/1999
Victor A. McKusick - updated: 1/21/1999
Victor A. McKusick - updated: 10/13/1998
Victor A. McKusick - updated: 8/28/1998
Victor A. McKusick - updated: 7/20/1998

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

*FIELD* ED
carol: 11/05/2013
carol: 11/4/2013
ckniffin: 10/30/2013
tpirozzi: 6/27/2013
mgross: 2/3/2009
alopez: 1/23/2007
terry: 1/19/2007
alopez: 9/7/2006
wwang: 11/18/2005
terry: 11/16/2005
terry: 4/6/2005
tkritzer: 9/20/2004
tkritzer: 9/10/2004
cwells: 7/15/2003
terry: 7/11/2003
carol: 12/13/2001
mcapotos: 12/7/2001
mgross: 1/24/2001
terry: 1/23/2001
mcapotos: 4/6/2000
terry: 3/8/2000
terry: 3/7/2000
alopez: 6/22/1999
jlewis: 6/17/1999
terry: 6/9/1999
carol: 4/8/1999
terry: 3/22/1999
carol: 2/5/1999
terry: 2/1/1999
terry: 1/21/1999
carol: 10/18/1998
terry: 10/13/1998
alopez: 8/31/1998
terry: 8/28/1998
carol: 7/21/1998
terry: 7/20/1998
dholmes: 12/30/1997
alopez: 6/11/1997
mimman: 2/8/1996
davew: 8/17/1994
terry: 5/7/1994
warfield: 4/15/1994
carol: 9/1/1993
supermim: 3/17/1992
carol: 2/6/1991

MIM 603930
*RECORD*
*FIELD* NO
603930
*FIELD* TI
*603930 GEPHYRIN; GPHN
;;GPH; GEPH;;
KIAA1385
MLL/GPHN FUSION GENE, INCLUDED
*FIELD* TX
read more
DESCRIPTION

The GPHN gene encodes gephyrin, an organizational protein that clusters
and localizes the inhibitory glycine and GABA receptors to the
microtubular matrix of the neuronal postsynaptic membrane (summary by
Rees et al., 2003).

To integrate signals from the many synaptic connections on its cell body
and dendrites rapidly and specifically, a neuron anchors high
concentrations of receptors at postsynaptic sites, matching the correct
receptor with the neurotransmitter released from the presynaptic
terminal. Receptor-associated proteins are thought to be involved in
forming these postsynaptic specializations, possibly by linking the
receptor to the postsynaptic cytoskeleton (Kirsch et al., 1993).
Gephyrin is essential for both the postsynaptic localization of
inhibitory neurotransmitter receptors in the central nervous system and
the biosynthesis of the molybdenum cofactor (MoCo) in different
peripheral organs (Stallmeyer et al., 1999).

CLONING

Prior et al. (1992) cloned the rat gene encoding a 93-kD protein that is
associated with the mammalian inhibitory glycine receptor (see 138492).
They designated this protein 'gephyrin,' from the Greek word meaning
'bridge,' because it binds with high affinity to polymerized tubulin,
suggesting that it may serve as a receptor-microtubule linker.

Ramming et al. (2000) described gephyrin splice variants that were
differentially expressed in nonneural tissues and different regions of
the adult mouse brain. They found that the mouse gephyrin gene shows a
highly mosaic organization, with 8 of its 29 exons corresponding to an
alternatively spliced region identified by cDNA sequencing. The N- and
C-terminal domains of gephyrin, encoded by exons 3-7 and 16-29,
respectively, displayed sequence similarities to bacterial,
invertebrate, and plant proteins involved in Moco biosynthesis, whereas
the central exons 8, 13, and 14 encode motifs that may mediate
oligomerization and tubulin binding. The data were consistent with the
evolution of gephyrin from a Moco biosynthetic protein by insertion of
protein interaction sequences.

By searching databases for sequences homologous to rat Geph, Reiss et
al. (2001) identified a brain tissue cDNA containing the complete coding
sequence of human GPHN.

Rees et al. (2003) isolated gephyrin cDNAs and by RT-PCR analysis of
human tissues demonstrated the presence of 5 alternatively spliced GPHN
exons concentrated in the central linker region of the gene. This region
generated 11 distinct GPHN transcript isoforms, with 10 being specific
to neuronal tissue.

GENE STRUCTURE

Reiss et al. (2001) determined that the GPHN gene contains 22 exons
spanning approximately 375 kb.

MAPPING

By genomic sequence analysis, Reiss et al. (2001) mapped the GPHN gene
to chromosome 14.

GENE FUNCTION

Kirsch et al. (1993) demonstrated that gephyrin is essential for
localizing the inhibitory glycine receptor to presumptive postsynaptic
plasma membrane specializations. Essrich et al. (1998) found that
gephyrin is also required for clustering and postsynaptic localization
of GABA(A) receptors. Sabatini et al. (1999) determined that gephyrin
interacts with RAFT1 (FRAP; 601231) in mammalian cells. RAFT1 is an ATM
(607585)-related protein that appears to participate in
mitogen-stimulated signaling pathways that control mRNA translation.
RAFT1 mutants that could not associate with gephyrin failed to signal to
downstream molecules. Sabatini et al. (1999) concluded that gephyrin
plays a role in signal transduction. They reported that all tissues
examined, including a human embryonic kidney cell line, contained RAFT1
and gephyrin.

Prior et al. (1992) noted that the C-terminal region of rat gephyrin
shares 36% amino acid identity with the E. coli ChlE (MoeA) protein,
which is thought to be involved in bacterial molybdopterin biosynthesis.
Stallmeyer et al. (1999) stated that the N-terminal region of gephyrin
is homologous to MogA, a second E. coli molybdenum cofactor (MoCo)
biosynthesis protein. They demonstrated that gephyrin binds with high
affinity to molybdopterin, the metabolic precursor of Moco. Gephyrin
expression reconstituted Moco biosynthesis in Moco-deficient bacteria, a
molybdenum-dependent mouse cell line, and a Moco-deficient plant mutant.
Stallmeyer et al. (1999) concluded that gephyrin plays a role in Moco
biosynthesis.

Butler et al. (2000) identified high-titer autoantibodies directed
against GPH in a patient with mediastinal cancer and clinical features
of stiff-man syndrome (184850). Their findings provided evidence for a
link between autoimmunity directed against components of inhibitory
synapses and neurologic conditions characterized by chronic rigidity and
spasms.

MOLECULAR GENETICS

The sequence of gephyrin shares homology with the proteins necessary for
the biosynthesis of MoCo: MoCo synthesis-1 (MOCS1; 603707) and MoCo
synthesis-2 (MOCS2; 603708). Because gephyrin expression can rescue a
MoCo-deficient mutation in bacteria, plants, and a murine cell line, it
is clear that gephyrin also plays a role in MoCo biosynthesis. Human
molybdenum cofactor deficiency is a fatal disease resulting in severe
neurologic damage and death in early childhood. Most patients harbor
MOCS1 mutations, which prohibit the formation of a precursor, or carry
MOCS2 mutations, which abrogate precursor conversion to molybdopterin.
In a patient with symptoms typical of molybdenum cofactor deficiency
belonging to complementation group C (MOCODC; 615501), Reiss et al.
(2001) identified a homozygous deletion in the GEPH gene (603930.0001).
Biochemical studies of the patient's fibroblasts demonstrated that
gephyrin catalyzes the insertion of molybdenum into molybdopterin and
suggested that this novel form of molybdenum cofactor deficiency might
be curable by molybdate supplementation.

In an Algerian girl with MOCODC, Reiss et al. (2011) identified a
homozygous mutation in the GPHN gene (D580A; 603930.0002).

For discussion of a possible role of variation in the GPHN gene in
hyperekplexia (see 149400), see 603930.0002.

CYTOGENETICS

- The MLL/GPHN Fusion Gene

Eguchi et al. (2001) found that the gephyrin gene can partner with MLL
(159555) in leukemia associated with the translocation
t(11;14)(q23;q24). The child in whom this translocation was discovered
showed signs of acute undifferentiated leukemia 3 years after intensive
chemotherapy that included the topoisomerase II inhibitor VP16. The AT
hook motifs and a DNA methyltransferase homology domain of the MLL gene
were fused to the C-terminal half of the gephyrin gene, including the
presumed tubulin-binding site and a domain homologous to the E. coli
molybdenum cofactor biosynthesis protein. Eguchi et al. (2001) suggested
that MLL-GPHN may have been generated by the chemotherapeutic agent,
followed by error-prone DNA repair via nonhomologous end-joining.

The MLL (mixed lineage leukemia) gene forms chimeric fusions with a
diverse set of partner genes as a consequence of chromosome
translocations in leukemia. In several fusion partners, a
transcriptional activation domain appears to be essential for conferring
leukemogenic capacity on MLL protein. Other fusion partners, however,
lack such domains. Eguchi et al. (2004) showed that gephyrin, a neuronal
receptor assembly protein and rare fusion partner of MLL in leukemia,
has the capacity as an MLL-GPHN chimera to transform hematopoietic
progenitors, despite lack of transcriptional activity. They found that a
small 15-amino acid tubulin-binding domain of GPHN is necessary and
sufficient for this activity in vitro and in vivo. This domain also
confers oligomerization capacity on MLL protein, suggesting that such
activity may contribute critically to leukemogenesis. The transduction
of MLL-GPHN into hematopoietic progenitor cells caused myeloid and
lymphoid lineage leukemias in mice, suggesting that MLL-GPHN can target
multipotent progenitor cells.

- Possible Association With Neuropsychiatric Disorders

Lionel et al. (2013) presented evidence that heterozygous deletions of
exons 3 to 5 of the GPHN gene may play a role in the risk for
neurodevelopmental disorders, particularly autism spectrum disorders
(ASD; see 209850) and schizophrenia (SCZD; see 181500). The GPHN gene
was selected for study because of its functional links with several
synaptic proteins that have been implicated in neurodevelopmental
disorders, including NLGN4 (300427) and NRXN2 (600566), as well as its
role in receptor stability at the synapse. Copy number variant analysis
identified heterozygous deletions at chromosome 14q23.3 interrupting
multiple exons of the GPHN gene in 5 of 5,384 individuals from cohorts
of patients with ASD, schizophrenia, and seizure disorders. A sixth
patient with schizophrenia and a heterozygous deletion affecting the
GPHN gene was also included in the study; this patient had previously
been reported (International Schizophrenia Consortium, 2008). The
deletions ranged in size from 183 to 357 kb; 1 breakpoint was shared by
3 patients. No exonic deletions at the GPHN locus were reported in the
Database of Genomic Variants, and CNVs at this locus were only found in
3 of 27,019 controls. The frequency of deletions was significantly
greater in patients (6 of 8,775) compared to controls (3 of 27,019, p =
0.009). Three of the deletions were proven to occur de novo in patients
with ASD, ASD with seizures, and schizophrenia, respectively. Parental
information was not available from the fourth patient, who had seizures.
A deletion found in a fifth patient, who had ASD, was inherited from a
father with subclinical social skills; there was significant psychiatric
history on both sides of the family. The sixth patient, who had
schizophrenia, inherited the deletion from an unaffected mother whose
mother reportedly had schizophrenia. The common region of overlap
encompassed exons 3 to 5 of the GPHN gene, corresponding to the coding
segment of the G domain, which is vital to the formation of gephyrin
scaffolds. Lionel et al. (2013) pointed to the study of Forstera et al.
(2010), who found expression of abnormally spliced GPHN mRNA in the
hippocampus of patients with temporal lobe epilepsy (see 600512) in the
absence of GPHN mutations. The splice variants lacked several exons
corresponding to the G domain, and the aberrant protein variants were
unable to form trimers. The abnormal variants acted in a
dominant-negative manner, resulting in a depletion of GABA receptor
cluster density and reduced GABAergic postsynaptic current amplitudes.
Forstera et al. (2010) concluded that expression of these variant GPHN
isoforms may reduce seizure threshold by reducing inhibitory currents
under certain physiologic conditions.

ANIMAL MODEL

Feng et al. (1998) used gene targeting to disrupt the mouse gephyrin
gene. Homozygous gephyrin-null mutant mice were born without apparent
developmental abnormalities but died within 1 day. Neonatal mutant
animals responded in an exaggerated way to a light touch on the skin,
becoming rigid and hyperextended and having difficulty breathing. Using
the mutant animals, the authors demonstrated that gephyrin is required
both for synaptic clustering of glycine receptors in spinal cord and for
molybdoenzyme activity in nonneural tissues. To determine whether the
neurologic symptoms were due to disruption of glycinergic synapses or to
a molybdenum cofactor deficiency, Feng et al. (1998) injected neonatal
mice with strychnine, a specific antagonist of the inhibitory glycine
receptor. The injection phenocopied the motor symptoms of gephyrin
deficiency, consistent with the idea that the phenotype is primarily
attributable to the failure of glycinergic synaptic activity. The mutant
phenotype resembled that of human patients with hereditary molybdenum
cofactor deficiency (see 615501) and hyperekplexia (see 149400), leading
the authors to suggest that gephyrin function may be impaired in both
diseases.

*FIELD* AV
.0001
MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP C
GPHN, EX2-3DEL

Reiss et al. (2001) studied the last of 3 affected infants born to a
Danish mother and father who were cousins. All 3 died in the neonatal
period (at day 12, 29, and 3, respectively), with symptoms identical to
those of molybdenum cofactor (MoCo) deficiency (MOCODC; 615501). Three
other pregnancies of the mother resulted in 2 healthy sibs and 1
spontaneous abortion. The first affected infant was a boy; the other 2
were girls. All showed hypotonia combined with hyperreflexia, as well as
tonic-clonic convulsions. Fibroblasts of the third infant were used to
verify molybdenum cofactor deficiency by biochemical and in vitro
complementation assays and to isolate DNA for genetic analysis. Reiss et
al. (2001) identified a deletion of exons 2 and 3 of the GPHN gene,
resulting in a frameshift after only 21 codons of normal coding
sequence.

.0002
VARIANT OF UNKNOWN SIGNIFICANCE
GPHN, ASN10TYR

This variant is classified as a variant of unknown significance because
its contribution to hyperekplexia has not been confirmed.

In 1 of 38 unrelated patients with hyperekplexia (see 149400), Rees et
al. (2003) detected a heterozygous 28A-T transversion in exon 1 of the
GPHN gene, resulting in an asn10-to-tyr (N10Y) substitution at the
extreme N terminus. The N10Y variant was not found in 94 controls. The
GPHN gene was chosen for sequencing after it was shown to interact with
the GLRB (138492) subunit. The N10Y substitution is located 5 residues
upstream from a putative region important for protein interactions;
however, in vitro functional expression studies in HEK293 cells
suggested that the variant did not affect the structural lattices formed
by gephyrin or interrupt its interactions with GLRB. The variant protein
did not interrupt cell surface clustering. Thus, the functional effect
of the variant remained elusive.

.0003
MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP C
GPHN, ASP580ALA

In a girl, born of consanguineous Algerian parents, with molybdenum
cofactor deficiency of complementation group C (MOCODC; 615501), Reiss
et al. (2011) identified a homozygous c.1739A-C transversion in exon 18
of the GPHN gene, resulting in an asp580-to-ala (D580A) substitution at
a highly conserved residue in the E domain. The unaffected parents were
heterozygous for the mutation. The E domain is believed to hydrolyze
adenylylated molybdopterin while inserting the molybdenum to yield
active cofactor. Accordingly, sulfite oxidase activity in patient
fibroblasts could not be detected even after incubation with molybdate.
The patient presented as a neonate with poor feeding, hypotonia, and
intractable seizures. At age 2 years, she had spasticity and lack of
psychomotor development.

*FIELD* RF
1. Butler, M. H.; Hayashi, A.; Ohkoshi, N.; Villmann, C.; Becker,
C.-M.; Feng, G.; De Camilli, P.; Solimena, M.: Autoimmunity to gephyrin
in stiff-man syndrome. Neuron 26: 307-312, 2000.

2. Eguchi, M.; Eguchi-Ishimae, M.; Greaves, M.: The small oligomerization
domain of gephyrin converts MLL to an oncogene. Blood 103: 3876-3882,
2004.

3. Eguchi, M.; Eguchi-Ishimae, M.; Seto, M.; Morishita, K.; Suzuki,
K.; Ueda, R.; Ueda, K.; Kamada, N.; Greaves, M.: GPHN, a novel partner
gene fused to MLL in a leukemia with t(11;14)(q23;q24). Genes Chromosomes
Cancer 32: 212-221, 2001.

4. Essrich, C.; Lorez, M.; Benson, J. A.; Fritschy, J.-M.; Luscher,
B.: Postsynaptic clustering of major GABA(A) receptor subtypes requires
the gamma-2 subunit and gephyrin. Nature Neurosci. 1: 563-571, 1998.

5. Feng, G.; Tintrup, H.; Kirsch, J.; Nichol, M. C.; Kuhse, J.; Betz,
H.; Sanes, J. R.: Dual requirement for gephyrin in glycine receptor
clustering and molybdoenzyme activity. Science 282: 1321-1324, 1998.

6. Forstera, B.; Belaidi, A. A.; Juttner, R.; Bernert, C.; Tsokos,
M.; Lehmann, T.-N.; Horn, P.; Dehnicke, C.; Schwarz, G.; Meier, J.
C.: Irregular RNA splicing curtails postsynaptic gephyrin in the
cornu ammonis of patients with epilepsy. Brain 133: 3778-3794, 2010.

7. International Schizophrenia Consortium: Rare chromosomal deletions
and duplications increase risk of schizophrenia. Nature 455: 237-241,
2008.

8. Kirsch, J.; Wolters, I.; Triller, A.; Betz, H.: Gephyrin antisense
oligonucleotides prevent glycine receptor clustering in spinal neurons. Nature 366:
745-748, 1993.

9. Lionel, A. C.; Vaags, A. K.; Sato, D.; Gazzellone, M. J.; Mitchell,
E. B.; Chen, H. Y.; Costain, G.; Walker, S.; Egger, G.; Thiruvahindrapuram,
B.; Merico, D.; Prasad, A.; and 20 others: Rare exonic deletions
implicate the synaptic organizer gephyrin (GPHN) in risk for autism,
schizophrenia and seizures. Hum. Molec. Genet. 22: 2055-2066, 2013.

10. Prior, P.; Schmitt, B.; Grenningloh, G.; Pribilla, I.; Multhaup,
G.; Beyreuther, K.; Maulet, Y.; Werner, P.; Langosch, D.; Kirsch,
J.; Betz, H.: Primary structure and alternative splice variants of
gephyrin, a putative glycine receptor-tubulin linker protein. Neuron 8:
1161-1170, 1992.

11. Ramming, M.; Kins, S.; Werner, N.; Hermann, A.; Betz, H.; Kirsch,
J.: Diversity and phylogeny of gephyrin: tissue-specific splice variants,
gene structure, and sequence similarities to molybdenum cofactor-synthesizing
and cytoskeleton-associated proteins. Proc. Nat. Acad. Sci. 97:
10266-10271, 2000.

12. Rees, M. I.; Harvey, K.; Ward, H.; White, J. H.; Evans, L.; Duguid,
I. C.; Hsu, C. C.-H.; Coleman, S. L.; Miller, J.; Baer, K.; Waldvogel,
H. J.; Gibbon, F.; Smart, T. G.; Owen, M. J.; Harvey, R. J.; Snell,
R. G.: Isoform heterogeneity of the human gephyrin gene (GPHN), binding
domains to the glycine receptor, and mutation analysis in hyperekplexia. J.
Biol. Chem. 278: 24688-24696, 2003.

13. Reiss, J.; Gross-Hardt, S.; Christensen, E.; Schmidt, P.; Mendel,
R. R.; Schwarz, G.: A mutation in the gene for the neurotransmitter
receptor-clustering protein gephyrin causes a novel form of molybdenum
cofactor deficiency. Am. J. Hum. Genet. 68: 208-213, 2001.

14. Reiss, J.; Lenz, U.; Aquaviva-Bourdain, C.; Joriot-Chekaf, S.;
Mention-Mulliez, K.; Holder-Espinasse, M.: A GPHN point mutation
leading to molybdenum cofactor deficiency. (Letter) Clin. Genet. 80:
598-599, 2011.

15. Sabatini, D. M.; Barrow, R. K.; Blackshaw, S.; Burnett, P. E.;
Lai, M. M.; Field, M. E.; Bahr, B. A.; Kirsch, J.; Betz, H.; Snyder,
S. H.: Interaction of RAFT1 with gephyrin required for rapamycin-sensitive
signaling. Science 284: 1161-1164, 1999.

16. Stallmeyer, B.; Schwarz, G.; Schulze, J.; Nerlich, A.; Reiss,
J.; Kirsch, J.; Mendel, R. R.: The neurotransmitter receptor-anchoring
protein gephyrin reconstitutes molybdenum cofactor biosynthesis in
bacteria, plants, and mammalian cells. Proc. Nat. Acad. Sci. 96:
1333-1338, 1999.

*FIELD* CN
Cassandra L. Kniffin - updated: 10/30/2013
Cassandra L. Kniffin - updated: 5/8/2012
Victor A. McKusick - updated: 8/9/2006
Victor A. McKusick - updated: 6/30/2006
Victor A. McKusick - updated: 10/6/2004
Victor A. McKusick - updated: 7/11/2003
Carol A. Bocchini - reorganized: 7/8/2002
Victor A. McKusick - updated: 12/13/2001
Dawn Watkins-Chow - updated: 10/22/2001
Victor A. McKusick - updated: 1/23/2001
Victor A. McKusick - updated: 10/11/2000

*FIELD* CD
Rebekah S. Rasooly: 6/22/1999

*FIELD* ED
carol: 11/06/2013
carol: 11/5/2013
carol: 11/4/2013
ckniffin: 10/30/2013
carol: 6/5/2012
carol: 5/9/2012
ckniffin: 5/8/2012
carol: 8/11/2006
terry: 8/9/2006
alopez: 6/30/2006
terry: 6/30/2006
alopez: 10/8/2004
terry: 10/6/2004
cwells: 7/15/2003
terry: 7/11/2003
ckniffin: 3/11/2003
carol: 7/8/2002
mcapotos: 12/18/2001
terry: 12/13/2001
carol: 10/23/2001
carol: 10/22/2001
mgross: 1/24/2001
terry: 1/23/2001
joanna: 10/17/2000
carol: 10/13/2000
terry: 10/11/2000
alopez: 12/14/1999
alopez: 6/23/1999
alopez: 6/22/1999