GPHN
protein-codinggephyrin
Gene summary
This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~674.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014212
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0021022
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014212
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0014212
Submitter: ClinGen
*GPHN* was first reported in relation to autosomal recessive molybdenum cofactor deficiency type C in 2001 (Reiss et al., PMID: 11095995). Molybdenum cofactor deficiency type C (MOCODC) is characterized by refractory neonatal seizures, dysmorphic features, ocular lens dislocation, and a characteristic urinary profile indicative of an underlying biochemical dysfunction (PMID: 33017596). The underlying mechanism is a failure to synthesize molybdenum cofactor, leading to loss of function of the enzymes sulfite oxidase, xanthine oxidase, and aldehyde oxidase (PMID: 33017596). Lumping and Splitting: *GPHN* encodes the gephyrin protein, which has two catalytically active domains that both participate in molybdenum cofactor biosynthesis. This protein also forms oligomeric clusters that act as scaffolds to promote the clustering of glycine and GABA type A receptors at the postsynaptic membrane of inhibitory neurons, a process that occurs independent of enzymatic activity. Heterozygous *GPHN* variants have been reported in individuals with complex neurodevelopmental disorders, but it is unclear at this time whether these variants are truly causative. Conversely, MOCODC is an autosomal recessive disease driven by loss of gephyrin enzyme activity. Therefore, this split curation only includes cases of confirmed molybdenum cofactor deficiency type C. Variants in this gene have been reported in two probands in two publications (PMID: 11095995, 22040219). Co-segregation with disease has not been observed in the literature. The mechanism of disease is biallelic loss of function. This gene-disease association is also supported by in vitro functional assays and an animal model (PMID: 9812897, 11095995, 33017596). Molybdenum cofactor synthesis was completely absent in fibroblasts from a MOCODC patient homozygous for a predicted null *GPHN* allele. Homozygous knock-out of the homologous gene in mice leads to the combined loss of sulfite oxidase and xanthine reductase. Further, these mice fail to thrive, have a significantly reduced lifespan, and exhibit spasticity reminiscent of the seizures observed in MOCODC patients. In summary, there is moderate evidence to support the gene-disease relationship between *GPHN* and autosomal recessive molybdenum cofactor deficiency type C. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has yet emerged. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on 5/12/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014212
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014212
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014212
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: In Hyperekplexia, autosomal dominant, evidence for pathogenicity is unclear (though multiple medical treatments, including clonazepam may be beneficial)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GPHN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020806.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 9 | 173 | 1 | 183 | ||
| missense | 4 | 332 | 9 | 345 | ||
| nonsense | 7 | 3 | 5 | 15 | ||
| start loss | 0 | |||||
| frameshift | 12 | 2 | 2 | 16 | ||
| splice donor/acceptor (+/-2bp) | 17 | 6 | 23 | |||
| Total | 23 | 22 | 354 | 182 | 1 | 582 |
Highest pathogenic variant AF is 0.000033474484
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_065857.1 | 23 | MANE Select | |
| Ensembl | ENSP00000417901.1 | 23 | MANE Select | |
| RefSeq | NP_001019389.1 | 22 | Standard | |
| RefSeq | NP_001364443.1 | 25 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Folate biosynthesis - Homo sapiens (human)
- GABAergic synapse - Homo sapiens (human)
- Splicing factor NOVA regulated synaptic proteins
- GABA receptor Signaling
- gamma-aminobutyric acid receptor life cycle pathway
Biological Process
- Mo-molybdopterin cofactor biosynthetic process
- establishment of synaptic specificity at neuromuscular junction
- response to metal ion
- molybdenum incorporation into molybdenum-molybdopterin complex
- molybdopterin cofactor biosynthetic process
Molecular Function
- protein binding
- ATP binding
- nitrate reductase activity
- molybdopterin cofactor binding
- metal ion binding
Cellular Component
- cytoplasm
- cytosol
- cytoskeleton
- plasma membrane
- postsynaptic density
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000478722
- Coding exons
- 23
- Length
- 674396
- Individuals with no LoFs
- 125726
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 15
- Defined
- 125742
- p
- 0.0000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.44 | 239 | 443 | 0.540 | 0.0000241 | 5007 |
| Missense (PolyPhen) | 92 | 221.81 | 0.41478 | 2436 | ||
| Synonymous | 0.205 | 143 | 146 | 0.978 | 0.00000749 | 1558 |
| Loss of Function | 5.72 | 3 | 43.9 | 0.0683 | 0.00000240 | 494 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.000062 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.00036 | 0.00033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Microtubule-associated protein involved in membrane protein-cytoskeleton interactions. It is thought to anchor the inhibitory glycine receptor (GLYR) to subsynaptic microtubules. Catalyzes two steps in the biosynthesis of the molybdenum cofactor. In the first step, molybdopterin is adenylated. Subsequently, molybdate is inserted into adenylated molybdopterin and AMP is released. {ECO:0000269|PubMed:26613940}.;
- Disease
- DISEASE: Molybdenum cofactor deficiency, complementation group C (MOCODC) [MIM:615501]: A form of molybdenum cofactor deficiency, an autosomal recessive metabolic disorder leading to the pleiotropic loss of molybdoenzyme activities. It is clinically characterized by onset in infancy of poor feeding, intractable seizures, severe psychomotor retardation, and death in early childhood in most patients. {ECO:0000269|PubMed:11095995, ECO:0000269|PubMed:22040219, ECO:0000269|PubMed:26613940}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.409
Intolerance Scores
- LoFtool
- 0.0473
- RVIS EVS
- 0.06
- RVIS percentile EVS
- 58.74
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.881
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |