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Normal Function
The GPHN gene provides instructions for making a protein called gephyrin, which has two major functions in the body: the protein aids in the formation (biosynthesis) of a molecule called molybdenum cofactor, and it also plays a role in communication between nerve cells (neurons).
Gephyrin performs the final two steps in molybdenum cofactor biosynthesis. Molybdenum cofactor, which contains the element molybdenum, is essential to the function of several enzymes called sulfite oxidase, aldehyde oxidase, xanthine dehydrogenase, and mitochondrial amidoxime reducing component (mARC). These enzymes help break down (metabolize) different substances in the body, some of which are toxic if not metabolized.
Gephyrin also plays an important role in neurons. Communication between neurons depends on chemicals called neurotransmitters. To relay signals, a neuron releases neurotransmitters, which attach to receptor proteins on neighboring neurons. Gephyrin anchors certain receptor proteins to the correct location in neurons so that the receptors can receive the signals relayed by neurotransmitters.
Health Conditions Related to Genetic Changes
Molybdenum cofactor deficiency
GPHN gene mutations cause a disorder called molybdenum cofactor deficiency. This disorder is characterized by seizures that begin early in life and brain dysfunction that worsens over time (encephalopathy); the condition is usually fatal by early childhood. At least two mutations in the GPHN gene have been found to cause a form of the disorder designated type C or complementation group C. This is the rarest form of the condition, affecting only a small number of individuals.
The GPHN gene mutations involved in molybdenum cofactor deficiency likely reduce or eliminate the function of gephyrin. The known mutations impair gephyrin's ability to perform one or both of the final two steps of molybdenum cofactor biosynthesis. Without the cofactor, the metabolic enzymes that rely on it cannot function.
The resulting loss of enzyme activity leads to buildup of certain chemicals, including sulfite, S-sulfocysteine, xanthine, and hypoxanthine, and low levels of another chemical called uric acid. (Testing for these chemicals can help in the diagnosis of this condition.) Sulfite, which is normally broken down by sulfite oxidase, is toxic, especially to the brain. Researchers suggest that damage caused by the abnormally high levels of sulfite (and possibly other chemicals) leads to encephalopathy, seizures, and the other features of molybdenum cofactor deficiency.
More About This Health ConditionOther Names for This Gene
- GEPH
- gephyrin isoform 1
- gephyrin isoform 2
- GPH
- GPHRYN
- HKPX1
- KIAA1385
- MOCODC
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Belaidi AA, Schwarz G. Metal insertion into the molybdenum cofactor: product-substrate channelling demonstrates the functional origin of domain fusion in gephyrin. Biochem J. 2013 Feb 15;450(1):149-57. doi: 10.1042/BJ20121078. Citation on PubMed
- Mendel RR. The molybdenum cofactor. J Biol Chem. 2013 May 10;288(19):13165-72. doi: 10.1074/jbc.R113.455311. Epub 2013 Mar 28. Citation on PubMed or Free article on PubMed Central
- Reiss J, Gross-Hardt S, Christensen E, Schmidt P, Mendel RR, 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. 2001 Jan;68(1):208-13. doi: 10.1086/316941. Epub 2000 Nov 28. Citation on PubMed or Free article on PubMed Central
- 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. Clin Genet. 2011 Dec;80(6):598-9. doi: 10.1111/j.1399-0004.2011.01709.x. No abstract available. Citation on PubMed
- Saiyed T, Paarmann I, Schmitt B, Haeger S, Sola M, Schmalzing G, Weissenhorn W, Betz H. Molecular basis of gephyrin clustering at inhibitory synapses: role of G- and E-domain interactions. J Biol Chem. 2007 Feb 23;282(8):5625-32. doi: 10.1074/jbc.M610290200. Epub 2006 Dec 20. Citation on PubMed
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