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

Abstract

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.

Assessment of the genomic variation in a cattle population by re-sequencing of key animals at low to medium coverage

“…The UMD3.1 reference coordinates could be determined for 59 of the OMIA entries (Additional files 6 and 7). The 2bp deletion in MOCS1 responsible for Arachnomelia (OMIA 001541–9913; [20]) could be detected in a known heterozygous carrier of the defective variant. An amino acid exchange in RASGRP2 has been proposed to be the causal variant for a bleeding disorder in a Simmental animal (Thrombopathia, OMIA 001003–9913; [21]).…”

Normalization of QT interval duration in a long QT syndrome patient during pregnancy and the postpartum period due to sex hormone effects on cardiac repolarization

“…This polymorphism is known to modulate the clinical phenotype in LQTS patients (QTc, arrhythmogenic events) 7 in a sex-specific manner, with additional QT prolongation in male but not in female patients, suggesting that this polymorphism might be susceptible to differential sex hormonal influence and could thus contribute to progesterone’s particularly pronounced QT interval–shortening effects observed in this patient.…”

“…However, a polymorphism in KCNE1 (Asp 85 Asn), the beta-subunit to KCNQ1 /KvLQT1, was detected. This polymorphism may play a role in drug-induced LQTS and has been observed more frequently in LQTS patients, where it contributes to the clinical phenotype (QT duration, arrhythmogenic events) 7 . Her father and mother have normal QTc durations, and there have been no confirmed cases of sudden death in the family, although her maternal uncle died in his 20s, reportedly of a seizure, and a maternal cousin drowned at 16 years of age with no apparent cause.…”

Genotype- and Phenotype-Guided Management of Congenital Long QT Syndrome

“…For example, common aminoacid altering single nucleotide polymorphisms (SNPs) in KCNE1 (D85N) [64], KCNH2 (K897T) [65], and SCN5A (H558R) [66, 67] exert modest electrophysiologic effects that can modulate the in vivo or in vitro phenotypic expression of certain LQT1-, LQT2-, and LQT3-causative mutations, respectively. Furthermore, recent studies have also identified a role for non-coding SNPs within critical genomic regions, such as the promoter or 3′ untranslated regions, known to regulate the expression of established LQTS-susceptibility genes (Table 2).…”