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GPHN
gephyrin
The GPHN gene provides instructions for the gephyrin protein, which is vital for synthesising molybdenum cofactor and plays a key role in neurotransmission within the brain. The GPHN gene encodes the gephyrin protein, essential for two distinct biological processes: the creation of molybdenum cofactor and the proper functioning of nerve cells.
GPHN is located on the long (q) arm of chromosome 14, at band 14q23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The GPHN gene, or gephyrin, is fundamental to human health due to its dual roles in molybdenum cofactor biosynthesis and neuronal communication. This gene provides the blueprint for the gephyrin protein, which carries out crucial enzymatic steps and acts as a scaffolding protein in the nervous system. Knowledge of GPHN helps clarify conditions linked to its dysfunction, such as Molybdenum Cofactor Deficiency.
What the gene does
The gephyrin protein, encoded by the GPHN gene, performs two primary functions in the body. Firstly, it is critical for the biosynthesis of molybdenum cofactor, executing the final two steps in its formation [PMID:28211448]. Molybdenum cofactor, which contains molybdenum, is essential for enzymes such as sulfite oxidase, aldehyde oxidase, xanthine dehydrogenase, and mitochondrial amidoxime reducing component (mARC). The resulting enzymes are responsible for clearing multiple compounds from the body, including those that would otherwise accumulate to toxic levels [PMID:20301295]. Secondly, gephyrin coordinates nerve cell communication by positioning neurotransmitter receptor complexes at precise synaptic sites on neurones. This ensures that receptors can efficiently receive signals transmitted by neurotransmitters, facilitating proper brain function [PMID:24942156].
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Chromosome location
The GPHN gene is located on chromosome 14, specifically at position 14q23.3. This chromosomal location indicates its precise address within the human genome, helping to identify its position relative to other genes and genetic markers.
Protein structure
The gephyrin protein is composed of 736 amino acids and exhibits a modular structure with several functional regions. It contains an MPT Mo-transferase region spanning amino acids 14-166, which is involved in molybdenum cofactor synthesis. An interaction with GABARAP region is located between amino acids 140-316. Additionally, there are two disordered regions, one from amino acids 181-232 and another from 260-290, which may contribute to its flexible interactions. The protein also features an MPT adenylyltransferase region from amino acids 326-736, also required for molybdenum cofactor biosynthesis.
Key variants
Genetic variations within the GPHN gene can affect the structure and function of the gephyrin protein. These variants may include changes such as single nucleotide polymorphisms, insertions, or deletions. Pathogenic variants can disrupt either the molybdenum cofactor synthesis pathway or the protein's role in neuronal signalling, leading to a range of potential health implications. Several pathogenic variants in GPHN have been documented in clinical databases. Detailed information on specific variants and their clinical significance is often compiled in genetic databases.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.168C>A | p.Tyr56Ter | Pathogenic/Likely pathogenic | ★★☆☆ | GPHN-Related Disorders |
c.577_578del | p.Leu193fs | Pathogenic/Likely pathogenic | ★★☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C |
GRCh37/hg19 14q23.3(chr14:67242514-67271090)x1 | - | Pathogenic | ★☆☆☆ | not specified |
g.(67147904_67243181)_(67243240_67291191)del | - | Pathogenic | ★☆☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C |
g.(?_67243162)_(67555812_?)del | - | Pathogenic | ★☆☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C |
g.(?_67431888)_(67525523_?)del | - | Pathogenic | ★☆☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C |
c.1463A>G | p.Gln488Arg | Pathogenic | ★☆☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C |
c.158dup | p.Ser54fs | Pathogenic | ★☆☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C |
c.744C>G | p.Tyr248Ter | Pathogenic | ★☆☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C |
c.747_748dup | p.Ser250fs | Pathogenic | ★☆☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the GPHN gene are primarily associated with Molybdenum Cofactor Deficiency, inherited in an autosomal recessive manner. This severe condition can lead to early-onset neurological symptoms, including seizures and progressive brain dysfunction (encephalopathy); the condition is often fatal in early childhood. The severity and specific clinical presentation can vary depending on the exact nature of the genetic variant.
Inheritance pattern
Conditions caused by pathogenic GPHN variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
GPHN is recognised within the NHS Genomic Medicine Service, indicating its clinical relevance in the UK. It is included on PanelApp for conditions such as Early onset or syndromic epilepsy, Likely inborn error of metabolism, and Undiagnosed metabolic disorders, all listed with a 'green' status, signifying strong evidence of gene-disease association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the GPHN gene?
The GPHN gene provides instructions for the gephyrin protein, which has two main functions: it is crucial for the biosynthesis of molybdenum cofactor and plays a significant role in anchoring receptor proteins in nerve cells to facilitate communication.
How is Molybdenum Cofactor Deficiency related to the GPHN gene?
Molybdenum Cofactor Deficiency is caused by pathogenic variants in the GPHN gene. These variants impair the gephyrin protein's ability to produce molybdenum cofactor, leading to severe neurological symptoms and metabolic dysfunction.
What inheritance pattern is associated with GPHN-related conditions?
Conditions linked to pathogenic variants in the GPHN gene, such as Molybdenum Cofactor Deficiency, are typically inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.
References
- Belaidi AA, Schwarz G. Metal insertion into the molybdenum cofactor: product-substrate channelling demonstrates the functional origin of domain fusion in gephyrin. The Biochemical journal. 2013. PMID: 23163752
- Mendel RR. The molybdenum cofactor. The Journal of biological chemistry. 2013. PMID: 23539623
- Reiss J, Lenz U, Aquaviva-Bourdain C. A GPHN point mutation leading to molybdenum cofactor deficiency. Clinical genetics. 2011. PMID: 22040219
- Saiyed T, Paarmann I, Schmitt B. Molecular basis of gephyrin clustering at inhibitory synapses: role of G- and E-domain interactions. The Journal of biological chemistry. 2007. PMID: 17182610
- Reiss J, Gross-Hardt S, Christensen E. A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency. American journal of human genetics. 2001. PMID: 11095995