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MOCS2
molybdenum cofactor synthesis 2
The MOCS2 gene provides instructions for creating two proteins essential for synthesising molybdenum cofactor, a vital molecule for several metabolic enzymes. The MOCS2 gene is crucial for the production of molybdenum cofactor, a compound required by various enzymes involved in breaking down toxic substances within the body.
MOCS2 is located on the long (q) arm of chromosome 5, at band 5q11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The MOCS2 gene, also known as molybdenum cofactor synthesis 2, is fundamental to human health due to its role in creating molybdenum cofactor. This cofactor is indispensable for the function of several enzymes that process different compounds in the body, some of which are toxic if not properly metabolised. Inherited changes in the MOCS2 gene are associated with Molybdenum Cofactor Deficiency, a serious metabolic disorder.
What the gene does
The MOCS2 gene directs the synthesis of two distinct proteins, MOCS2A and MOCS2B. These proteins combine to form an enzyme known as molybdopterin synthase. Molybdopterin synthase catalyses a critical step in the biosynthesis pathway of molybdenum cofactor [PMID:10712431]. This cofactor, which contains the element molybdenum, is essential for the activity of enzymes such as sulfite oxidase, aldehyde oxidase, xanthine dehydrogenase, and mitochondrial amidoxime reducing component (mARC) [PMID:11933182]. These enzymes are involved in metabolising various substances, and their proper function is crucial for preventing the accumulation of toxic compounds in the body.
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Chromosome location
The MOCS2 gene is situated on chromosome 5, specifically at position 5q11.2. This genomic location specifies where the gene resides within the human genome.
Protein structure
The MOCS2 gene encodes a protein that is 188 amino acids in length. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic changes, or variants, in the MOCS2 gene can impact its ability to produce functional molybdopterin synthase. Multiple pathogenic variants in MOCS2 have been identified that lead to Molybdenum Cofactor Deficiency. These variants are typically inherited in an autosomal recessive pattern.
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.106_107del | p.Met36fs | Pathogenic/Likely pathogenic | ★★☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1 |
c.118G>T | p.Glu40Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1 |
c.164C>G | p.Ser55Ter | Pathogenic | ★★☆☆ | not provided |
c.182_185del | p.Gln61fs | Pathogenic/Likely pathogenic | ★★☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1 |
c.304G>T | p.Glu102Ter | Pathogenic | ★★☆☆ | Combined molybdoflavoprotein enzyme deficiency |
c.367del | p.His123fs | Pathogenic | ★★☆☆ | not provided |
c.377+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1 |
c.469dup | p.Thr157fs | Pathogenic/Likely pathogenic | ★★☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1 |
c.33T>G | p.Tyr11Ter | Pathogenic | ★★☆☆ | Combined molybdoflavoprotein enzyme deficiency |
c.88C>T | p.Gln30Ter | Pathogenic | ★★☆☆ | Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1 |
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 MOCS2 gene are known to cause Molybdenum Cofactor Deficiency. This inherited condition is characterised by early-onset seizures and progressive brain dysfunction, often leading to a fatal outcome in early childhood [PMID:20301479]. The severity of the condition arises from the body's inability to properly metabolise certain toxic substances due to a lack of functional molybdenum cofactor.
Inheritance pattern
Conditions caused by pathogenic MOCS2 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
The MOCS2 gene is included in several NHS Genomic Medicine Service national test directories, reflecting its clinical significance within the UK. It is listed as 'green' in DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the MOCS2 gene?
The MOCS2 gene is responsible for producing two proteins, MOCS2A and MOCS2B, which combine to form molybdopterin synthase. This enzyme is crucial for synthesising molybdenum cofactor, a molecule vital for several metabolic enzymes.
What condition is associated with MOCS2 gene variants?
Variants in the MOCS2 gene are associated with Molybdenum Cofactor Deficiency. This is a severe inherited metabolic disorder primarily affecting neurological development.
How is Molybdenum Cofactor Deficiency inherited?
Molybdenum Cofactor Deficiency caused by MOCS2 variants follows an autosomal recessive inheritance pattern. This means an individual must inherit two pathogenic variants, one from each parent, to develop the condition.
References
- Mendel RR. The molybdenum cofactor. The Journal of biological chemistry. 2013. PMID: 23539623
- Leimkühler S, Charcosset M, Latour P. Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase. Human genetics. 2005. PMID: 16021469
- Leimkuhler S, Freuer A, Araujo JA. Mechanistic studies of human molybdopterin synthase reaction and characterization of mutants identified in group B patients of molybdenum cofactor deficiency. The Journal of biological chemistry. 2003. PMID: 12732628
- Reiss J, Johnson JL. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Human mutation. 2003. PMID: 12754701