Categories: Muscle phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 614160 (trait) , 601788 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2019

Species-specific description: Matika et al. (2019) concluded that "This MSTN mutation is an example of putative balancing selection in livestock, providing a plausible explanation for the lack of disrupting MSTN mutations in pigs despite many generations of selection for lean growth."

Inheritance: As reported by Matika et al. (2019): "The overall prevalence of leg weakness in the commercial cohort was 6.3% . . . . When only affected litters were considered, the mean proportion of affected piglets was 23% ± 0.7. This within-litter prevalence is consistent with the expectation under the hypothesis of a single recessive locus (i.e. 25%). Complex Bayesian segregation analysis . . . suggested that almost all the variation was explained by a single locus with almost no environmental variation. The estimate of the additive effect was 0.50 ± 0.001 and dominance effect was -0.50 ± 0.001, which is in precise agreement with a recessive locus model. Estimates of heritability for the leg weakness syndrome (analysed as a binary trait on the underlying liability scale) was high (0.57 ± 0.10 in the sire and dam model) with low (0.17 ± 0.02 and 0.11 ± 0.02) but significant effects observed for permanent environmental effects due to the dam and litter, respectively."

Mapping: Using homozygosity mapping, Matika et al. (2019) mapped this disorder to "a region of ~ 8.3 Mbp on SSC15" (86,745,668 to 95,062,143; Sscrofa11.1 reference genome assembly), which includes a likely candidate gene, namely MSTN.

Molecular basis: Whole genome sequence data from the candidate region in "ten cases, six presumed heterozygous carrier dams, and 22 controls" led Matika et al. (2019) to the identification of a likely causal variant: "a mutation in the third exon of the MSTN locus that results in the replacement of a codon for glutamic acid with a stop codon in exon 3 at position 274 (c.820G>T; p.E274*) . . . . The mutation is located in a region that is highly conserved across multiple species, and is predicted to result in truncation of the protein."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: As reported by Matika et al. (2019): "The leg weakness in the phenotyped animals was visually classified as normal or affected (0/1 respectively). The leg defect is characterised by the piglet not being able to straighten its legs to stand, this being most apparent for the front legs, and being slow to suckle. Detailed post mortems were conducted on two affected individuals but the results were ineffective in providing additional diagnostic aids. The Online Mendelian Inheritance in Animals database (OMIA: http://omia.org/OMIA000585/9823/) was searched for previous reports of leg weakness in pigs but the syndrome observed here did not appear. These problems frequently resulted in death from either starvation or being crushed by the sow."

Prevalence: As reported by Matika et al. (2019): "The MSTN mutation was in Hardy-Weinberg equilibrium in the population at birth, but significantly distorted amongst animals still in the herd at 110 kg, due to an absence of homozygous mutant genotypes. In heterozygous form, the MSTN mutation was associated with a major increase in muscle depth and decrease in fat depth, suggesting that the deleterious allele was maintained at moderate frequency due to heterozygous advantage (allele frequency, q = 0.22)."

Breed: Large White (Pig) (VBO_0001163).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: