A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses

Carrie J Finno, Giuliana Gianino, Sudeep Perumbakkam, Zoë J. Williams, Matthew H. Bordbari, Keri L. Gardner, Erin Burns, Sichong Peng, Sian A. Durward-Akhurst, Stephanie J. Valberg

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article number7
JournalSkeletal Muscle
Volume8
Issue number1
DOIs
StatePublished - Mar 6 2018

Fingerprint

Myositis
Missense Mutation
Horses
Mutation
Skeletal Muscle Myosins
Phenotype
Muscular Atrophy
Myosin Heavy Chains
Genome-Wide Association Study
Myosins
Haplotypes
Genes
Autoimmune Diseases
Single Nucleotide Polymorphism
Genome
Inflammation

Keywords

  • Equine
  • Genome-wide association
  • Immunology
  • Myopathy
  • Myosin heavy chain 1

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Finno, C. J., Gianino, G., Perumbakkam, S., Williams, Z. J., Bordbari, M. H., Gardner, K. L., ... Valberg, S. J. (2018). A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses. Skeletal Muscle, 8(1), [7]. https://doi.org/10.1186/s13395-018-0155-0

A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses. / Finno, Carrie J; Gianino, Giuliana; Perumbakkam, Sudeep; Williams, Zoë J.; Bordbari, Matthew H.; Gardner, Keri L.; Burns, Erin; Peng, Sichong; Durward-Akhurst, Sian A.; Valberg, Stephanie J.

In: Skeletal Muscle, Vol. 8, No. 1, 7, 06.03.2018.

Research output: Contribution to journalArticle

Finno, CJ, Gianino, G, Perumbakkam, S, Williams, ZJ, Bordbari, MH, Gardner, KL, Burns, E, Peng, S, Durward-Akhurst, SA & Valberg, SJ 2018, 'A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses', Skeletal Muscle, vol. 8, no. 1, 7. https://doi.org/10.1186/s13395-018-0155-0
Finno, Carrie J ; Gianino, Giuliana ; Perumbakkam, Sudeep ; Williams, Zoë J. ; Bordbari, Matthew H. ; Gardner, Keri L. ; Burns, Erin ; Peng, Sichong ; Durward-Akhurst, Sian A. ; Valberg, Stephanie J. / A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses. In: Skeletal Muscle. 2018 ; Vol. 8, No. 1.
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abstract = "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.",
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AU - Bordbari, Matthew H.

AU - Gardner, Keri L.

AU - Burns, Erin

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