Alternative titles; symbols
HGNC Approved Gene Symbol: MOCS2
SNOMEDCT: 1003368009;
Cytogenetic location: 5q11.2 Genomic coordinates (GRCh38) : 5:53,095,679-53,109,757 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q11.2 | Molybdenum cofactor deficiency B | 252160 | Autosomal recessive | 3 |
The MOCS2 gene encodes a protein involved in the synthesis of molybdenum cofactor (MoCo). MoCo synthesis is an ancient, ubiquitous, and highly conserved pathway leading to biochemical activation of molybdenum. In humans, MoCo is essential for the activities of sulfite oxidase (SUOX; 606887), xanthine dehydrogenase (XDH; 607633), and aldehyde oxidase (AOX1; 602841). MoCo biosynthesis involves formation of precursor Z by proteins encoded by MOCS1 (603707), the subsequent conversion of precursor Z to molybdopterin (MPT) by MPT synthase (MOCS2), and attachment of molybdenum to the dithiolene moiety of MPT by gephyrin (GPHN; 603930). MOCS2 is bicistronic, with overlapping ORFs encoding MOCS2A and MOCS2B, the 2 subunits of MPT synthase (Leimkuhler et al., 2003).
In E. coli, MPT synthase consists of small and large subunits encoded by the MoaD and MoaE genes, respectively. By searching an EST database for sequences similar to MoaE, followed by screening an adult liver cDNA library, Stallmeyer et al. (1999) cloned human MOCS2. The MOCS2 transcript is bicistronic and encodes the small and large subunits of MPT synthase in 2 different ORFs. The more 5-prime ORF encodes the small subunit, MOCS2A, a deduced 88-amino acid protein with a calculated molecular mass of 9.8 kD. The ORF for the large subunit, MOCS2B, overlaps the ORF for MOCS2A by 77 bp and encodes a deduced 188-amino acid protein with a calculated molecular mass of 20.8 kD. MOCS2B and its mammalian homologs have an N-terminal extension of about 40 amino acids that is not found in eubacteria homologs, and this extension represents the region where the MOCS2A and MOCS2B ORFs overlap. Northern blot analysis detected variable expression of a 1.35-kb transcript in all tissues examined. In vitro translation resulted in MOCS2A and MOCS2B proteins with apparent molecular masses of 10 and 21 kD, respectively, by SDS-PAGE.
Sloan et al. (1999) independently cloned MOCS2, which they called MOCO1. Northern blot analysis detected a 1.35-kb transcript in all tissues examined, with highest expression in heart and skeletal muscle.
Using RT-PCR, Hahnewald et al. (2006) identified 2 MOCS2 splice variants containing alternative first exons that determined expression of MOCS2A or MOCS2B.
Reiss et al. (1999) determined that the MOCS2 gene contains 7 exons. Exons 1 to 3 encode MOCS2A, and exons 3 to 7 encode MOCS2B.
Hahnewald et al. (2006) identified an alternative first exon, 1b, that is used exclusively by transcripts encoding MOCS2B. Exon 1a is used exclusively by transcripts encoding MOCS2A.
By PCR screening of a radiation-induced cell-hybrid panel, Reiss et al. (1999) mapped the MOCS2 gene to chromosome 5p11-q11, and linkage to an EST marker to 2 polymorphic DNA markers established the location as 5q11.
Using size exclusion chromatography, Leimkuhler et al. (2003) showed that separately purified MOCS2A and MOCS2B subunits formed dimers in solution. When mixed, they assembled into a tetrameric MPT synthase complex.
A thiocarboxylate group at the second glycine of the C-terminal gly-gly motif of the small subunit of E. coli MPT synthetase serves as the sulfur donor for the formation of the dithiolene group in MPT. Human MOCS2A has a C-terminal gly-gly motif, and Leimkuhler et al. (2003) demonstrated that thiocarboxylated MOCS2A plus MOCS2B catalyzed conversion of MPT from precursor Z.
Molybdenum cofactor deficiency is a rare autosomal recessive metabolic disorder characterized by neonatal onset of intractable seizures, opisthotonus, and facial dysmorphism associated with hypouricemia and elevated urinary sulfite levels. Affected individuals show severe neurologic damage and often die in early childhood. The disorder results from decreased activity of sulfite oxidase (SUOX; 606887) and xanthine dehydrogenase (XDH; 607633), both of which are dependent on molybdenum cofactor for activity. In 7 of 8 patients with molybdenum cofactor deficiency type B (MOCODB; 252160), Reiss et al. (1999) identified biallelic mutations in the MOCS2 gene (see, e.g., 603708.0001-603708.0005). A 2-bp deletion (726del2; 603708.0001) accounted for 50% (7 of 14) of identified alleles. Furthermore, a start-codon mutation and a missense mutation of a highly conserved amino acid residue were found. The locations of the mutations confirmed the important functional role of both MOCS2 ORFs. One of the patients with identified MOCS2 mutations had been classified as type B in complementation studies.
In a patient with molybdenum cofactor deficiency, Leimkuhler et al. (2005) identified a mutation in the MOCS2 gene that altered the stop codon of the MOCS2B ORF (X189Y; 603708.0008).
In a patient with molybdenum cofactor deficiency, Hahnewald et al. (2006) identified a 23-bp deletion in the MOCS2 gene (603708.0009) that removed the translation initiation site for MOCS2A. RT-PCR analysis showed a truncated MOCS2A transcript and a MOCS2B transcript of normal length. However, Western blot analysis revealed no MOCS2A protein and very little MOCS2B, suggesting that MOCS2B is degraded in the absence of MOCS2A.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human MOCS2 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In 4 patients with molybdenum cofactor deficiency type B (MOCODB; 252160), Reiss et al. (1999) identified a 2-bp deletion, 726del2, in the MOCS2 gene, removing the last 9 amino acids of the gene product. The mutation was found in homozygous state in 3 patients (1 French, 1 Portuguese, and 1 English) and in compound heterozygous state in a German patient with an E168K missense mutation (603708.0002). This deletion mutation accounted for 50% (7 of 14) of identified alleles.
Reiss and Johnson (2003) reported that the 726delAA frameshift deletion is the most common MOCS2B mutation, having been found on 11 of 28 alleles. They speculated that the prevalence of this mutation in port cities of Portugal, France, the Netherlands, and Germany raises the possibility of distribution by a merchant sailor.
In a German patient with molybdenum cofactor deficiency (MOCODB; 252160), Reiss et al. (1999) identified compound heterozygous mutations in the MOCS2 gene: a 726del2 mutation (603708.0001) on the paternal allele and a missense mutation, glu168 to lys (E168K), on the maternal allele. The E168K mutation affected the first nucleotide of exon 7 (GAA to AAA). E168 is one of the few extremely conserved residues in the large subunit of molybdopterin synthase and the amino acid substitution E168K was most likely sufficient for impairment of the protein's enzymatic activity. The substituted G, however, contributes to the consensus value of the splice site (Krawczak et al., 1992) and an additional effect on splicing efficiency is possible.
Leimkuhler et al. (2003) found that MOCS2B with the E168K mutation readily formed MPT synthase tetramers with MOCS2A. However, compared with the wildtype enzyme, only a small amount of precursor Z bound tetramers including MOCS2B-E168K, resulting in reduced MPT synthase activity.
In an Italian patient with molybdenum cofactor deficiency (MOCODB; 252160), Reiss et al. (1999) identified a homozygous 4-bp deletion, 533del4, in exon 5 of the MOCS2 gene.
In a Portuguese patient with molybdenum cofactor deficiency (MOCODB; 252160), Reiss et al. (1999) identified homozygosity for insertion of a C after nucleotide 252 (252insC) in exon 3 of the MOCS2 gene.
The 2 MOCS2 ORFs appear to be translated into 2 different proteins, MOCS2A and MOCS2B, from a single transcript with no alternative splicing involved (Stallmeyer et al., 1999). Reiss and Johnson (2003) stated that, consequently, the 252insC mutation, which falls in the overlap region of MOCS2A and MOCS2B and was identified in a single patient, is the only mutation that affects both MOCS2 ORFs.
In a Coptic Egyptian patient with molybdenum cofactor deficiency (MOCODB; 252160), Reiss et al. (1999) identified homozygosity for a start codon mutation, met1 to ile, in the MOCS2 gene.
Johnson et al. (2001) reported a 4-year-old patient with mild features of molybdenum cofactor deficiency (MOCODB; 252160), including mild developmental delay, but no seizures or lens dislocation. The patient was compound heterozygous for 2 single-base substitutions in the MOCS2 gene: a C-to-T transition at nucleotide 16 in exon 1, resulting in a gln6-to-ter (Q6X) mutation on one allele, and a G-to-T transversion at nucleotide 19 in exon 2, resulting in a val7-to-phe (V7F) mutation (603708.0007) on the other. The authors postulated that a low level of residual molybdopterin synthase activity derived from the V7F allele may have been responsible for the milder clinical symptoms.
For discussion of the val7-to-phe (V7F) mutation in the MCOS2 gene that was found in compound heterozygous state in a patient with mild features of molybdenum cofactor deficiency (MOCODB; 252160) by Johnson et al. (2001), see 603078.0006.
Leimkuhler et al. (2003) showed that neither the carboxylated nor the thiocarboxylated form of MOCS2A with the V7F mutation formed a complex with MOCS2B. A mixture of MOCS2A-V7F and MOCS2B showed very low MPT synthase activity compared with wildtype MPT synthase, although a hemisulfurated MPT intermediate was observed.
In a 9-month-old Mexican infant with molybdenum cofactor deficiency (MOCODB; 252160), Leimkuhler et al. (2005) identified an A-to-C transversion in exon 7 of the MOCS2 gene, resulting in a ter189-to-tyr (X189Y) substitution, predicted to add 18 amino acids to the C terminus of the MOCS2B protein. In vitro functional studies revealed that the elongated mutant did not form a complex with carboxylated MOCS2A and did not bind to precursor Z. The patient had an unusual phenotype with no evidence of seizure disorder, lens dislocation, or progressive psychomotor retardation. However, he had static encephalopathy, microcephaly, dysmorphic features, spastic quadriparesis, nystagmus, irritability, and diffuse cerebral atrophy.
In a Senegalese boy with molybdenum cofactor deficiency (MOCODB; 252160), Hahnewald et al. (2006) identified a 23-bp deletion at nucleotide 148 (148del23) in exon 1a of the MOCS2 gene. The deletion included the translation initiation site for MOCS2A. RT-PCR revealed an abnormal MOCS2A transcript and normal MOCS2B transcript in cultured skin fibroblasts, but Western blot analysis of liver showed no MOCS2A protein and low amounts of MOCS2B. The child was born to a nonconsanguineous couple and appeared healthy at birth. From the third day of life, he developed feeding difficulties, hypotonia, and drug-resistant tonic and clonic seizures, and he had elevated sulfite and diminished uric acid in urine. He died 21 days after birth from cardiorespiratory arrest.
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