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A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses
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A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses
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A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses
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Journal Article
A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses
2018
Overview
Background
The cause of immune-mediated myositis (IMM), characterized by recurrent, rapid-onset muscle atrophy in Quarter Horses (QH), is unknown. The histopathologic hallmark of IMM is lymphocytic infiltration of myofibers. The purpose of this study was to identify putative functional variants associated with equine IMM.
Methods
A genome-wide association (GWA) study was performed on 36 IMM QHs and 54 breed matched unaffected QHs from the same environment using the Equine SNP50 and SNP70 genotyping arrays.
Results
A mixed model analysis identified nine SNPs within a ~ 2.87 Mb region on chr11 that were significantly (
P
unadjusted
< 1.4 × 10
− 6
) associated with the IMM phenotype. Associated haplotypes within this region encompassed 38 annotated genes, including four myosin genes (
MYH1
,
MYH2
,
MYH3
, and
MYH13
). Whole genome sequencing of four IMM and four unaffected QHs identified a single segregating nonsynonymous E321G mutation in
MYH1
encoding myosin heavy chain 2X. Genotyping of additional 35 IMM and 22 unaffected QHs confirmed an association (
P
= 2.9 × 10
− 5
), and the putative mutation was absent in 175 horses from 21 non-QH breeds. Lymphocytic infiltrates occurred in type 2X myofibers and the proportion of 2X fibers was decreased in the presence of inflammation. Protein modeling and contact/stability analysis identified 14 residues affected by the mutation which significantly decreased stability.
Conclusions
We conclude that a mutation in
MYH1
is highly associated with susceptibility to the IMM phenotype in QH-related breeds. This is the first report of a mutation in
MYH1
and the first link between a skeletal muscle myosin mutation and autoimmune disease.
Publisher
BioMed Central,BioMed Central Ltd,BMC
