Report on a new patient with combined deficiencies of sulphite oxidase and xanthine dehydrogenase due to molybdenum cofactor deficiency

Endres, W.; Shin, Yoon S.; Gunther, Robert A.; Ibel, H.; Durán, Marinus; Wadman, S.K.

doi:10.1007/bf00441412

Cited by 34 publications

(22 citation statements)

References 14 publications

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“…In cattle the main predilection site of Moco-deficiency is the developing bone. Even though bone malformations are not common signs of Moco-deficiency in human and mice, rarely microcephaly and a prominent forehead are observed in patients with Moco- [25] and SOD-deficiency [26]. …”

Section: Discussionmentioning

confidence: 99%

Arachnomelia syndrome in Simmental cattle is caused by a homozygous 2-bp deletion in the molybdenum cofactor synthesis step 1 gene (MOCS1)

2011

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BackgroundArachnomelia syndrome is an autosomal recessive inherited disease in cattle. Affected calves die around birth and show malformations of the skeleton mainly affecting the legs, the spinal column and the skull. A number of arachnomelia syndrome affected Simmental calves were recently detected by a surveillance system of anomalies with a peak of more than 120 recorded cases in the year 2006. The causative mutation was previously mapped to a 9 cM-region on bovine chromosome 23. We herein report the fine-mapping and identification of the gene causing arachnomelia syndrome in Simmental cattle.ResultsBy using a dense set of markers, the arachnomelia syndrome linked region could be refined to 1.5 cM harbouring three protein coding genes. Comparative sequencing of these genes revealed a two-bp-deletion in the bovine MOCS1 gene resulting in a frame-shift and a premature termination codon. We genotyped affected calves and their ancestors and found that all affected were homozygous for the deletion whereas all carriers were heterozygous. Furthermore, cattle from the same population, but not directly related to known carriers mostly showed the wild type genotype.ConclusionsMOCS1 encodes two proteins that are involved in the first synthesis step of molybdenum cofactor. A non functional sulfite-oxydase, one of the enzymes requiring molybdenum cofactor, leads to a similar pathology in Brown Swiss cattle. In combination the perfect association of the mutation with the phenotype and the obvious disruption of protein translation provide strong evidence for the causality of the MOCS1 mutation. Our results are the first example for an oligogenic lethal inherited disease in cattle. Furthermore, they show the potential involvement of sulfite metabolism in aberrant bone development.

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Section: Discussionmentioning

confidence: 99%

Arachnomelia syndrome in Simmental cattle is caused by a homozygous 2-bp deletion in the molybdenum cofactor synthesis step 1 gene (MOCS1)

2011

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“…Supplementation of the fibroblast culture medium with 1mM molybdate restored the normal phenotype, indicating that molybdate supplementation might be of therapeutic benefit in patients with this unusual form of the disease. Molybdate therapy has been tried repeatedly in the past without success [Duran et al, 1978;Munnich et al, 1983;Endres et al, 1988;Bamforth et al, 1990]; however, the defects in these patients were not defined by mutational analysis, and it is likely that the mutations were in MOCS1 or MOCS2, which are more prevalent in the population and cannot be overcome by increased molybdate concentrations.…”

Section: Complementation Group B: Mocs2 Mutations and One Case Of Gepmentioning

confidence: 96%

Mutations in the molybdenum cofactor biosynthetic genesMOCS1, MOCS2, andGEPH

Reiss¹,

Johnson

2003

Hum. Mutat.

130

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Molybdenum cofactor deficiency in humans results in the loss of the activity of molybdoenzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. The resultant severe phenotype, which includes progressive neurological damage leading in most cases to early childhood death, results primarily from the deficiency of sulfite oxidase. All forms of molybdenum cofactor deficiency are inherited as autosomal recessive traits. The cofactor is an unstable reduced pterin with a unique four-carbon side chain, synthesized by a complex pathway that requires the products of at least four different genes (MOCS1, MOCS2, MOCS3, and GEPH). Disease-causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH. MOCS1 and MOCS2 have a bicistronic architecture; i.e., each gene encodes two proteins in different open reading frames. The protein products, MOCS1A and B and MOCS2A and B, are expressed either from different mRNAs generated by alternative splicing or by independent translation of a bicistronic mRNA. The gephyrin protein, encoded by a third locus, is required during cofactor assembly for insertion of molybdenum. A total of 32 different disease-causing mutations, including several common to more than one family, have been identified in molybdenum cofactor-deficient patients and their relatives.

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“…Later, these Mo-induced conditions of copper-deficiency revealed the pathology of two human Cu-homeostasis disorders: Menkes (Cu-deficiency) and Wilson's (Cu-overload) diseases [79]. Consequently, potent Cu-chelators such as tetrathiomolybdates were used to treat Wilson's disease and a number of other disorders that are linked to Cu-homeostasis, [91]. Magnetic resonance images at 11 days (C) and 3.5 months (D) of age show progressive brain atrophy and changes in the subcortical white matter [84].…”

Section: Molybdenum-iron and Molybdenum-copper Homeostasismentioning

confidence: 99%