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PLoS genetics2015; 11(4); e1005122; doi: 10.1371/journal.pgen.1005122

SERPINB11 frameshift variant associated with novel hoof specific phenotype in Connemara ponies.

Abstract: Horses belong to the order Perissodactyla and bear the majority of their weight on their third toe; therefore, tremendous force is applied to each hoof. An inherited disease characterized by a phenotype restricted to the dorsal hoof wall was identified in the Connemara pony. Hoof wall separation disease (HWSD) manifests clinically as separation of the dorsal hoof wall along the weight-bearing surface of the hoof during the first year of life. Parents of affected ponies appeared clinically normal, suggesting an autosomal recessive mode of inheritance. A case-control allelic genome wide association analysis was performed (ncases = 15, ncontrols = 24). Population stratification (λ = 1.48) was successfully improved by removing outliers (ncontrols = 7) identified on a multidimensional scaling plot. A genome-wide significant association was detected on chromosome 8 (praw = 1.37x10-10, pgenome = 1.92x10-5). A homozygous region identified in affected ponies spanned from 79,936,024-81,676,900 bp and contained a family of 13 annotated SERPINB genes. Whole genome next-generation sequencing at 6x coverage of two cases and two controls revealed 9,758 SNVs and 1,230 indels within the ~1.7-Mb haplotype, of which 17 and 5, respectively, segregated with the disease and were located within or adjacent to genes. Additional genotyping of these 22 putative functional variants in 369 Connemara ponies (ncases = 23, ncontrols = 346) and 169 horses of other breeds revealed segregation of three putative variants adjacent or within four SERPIN genes. Two of the variants were non-coding and one was an insertion within SERPINB11 that introduced a frameshift resulting in a premature stop codon. Evaluation of mRNA levels at the proximal hoof capsule (ncases = 4, ncontrols = 4) revealed that SERPINB11 expression was significantly reduced in affected ponies (p<0.001). Carrier frequency was estimated at 14.8%. This study describes the first genetic variant associated with a hoof wall specific phenotype and suggests a role of SERPINB11 in maintaining hoof wall structure.
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Publication Date: 2015-04-13 PubMed ID: 25875171PubMed Central: PMC4395385DOI: 10.1371/journal.pgen.1005122Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research paper discusses an inherited disease in Connemara ponies called Hoof Wall Separation Disease (HWSD) which affects the hoof wall. The researchers identified a genetic variant in the SERPINB11 gene associated with this disease.

Hoof Wall Separation Disease

  • The paper reports on a disease identified in Connemara ponies called HWSD. This disease shows itself during a pony’s first year of life, manifesting as a separation of the dorsal hoof wall, the area that bears most of the weight in the ponies’ limbs.
  • Despite the seriousness of this disease, the parents of the affected ponies showed no signs of it, leading the researchers to suspect that the disease followed an autosomal recessive pattern of inheritance.

Genetic Study

  • A genomic study was conducted to understand the underlying cause of HWSD. Genome-wide association analysis was performed using 15 cases and 24 controls.
  • Population stratification was improved by removing statistical outliers, resulting in an association being identified on chromosome 8.
  • A region in chromosome 8, spanning approximately 1.7 million base pairs, was found to be homozygous (containing two copies of the same allele for a single gene) in affected ponies. This region contained a group of 13 SERPINB genes.

Whole Genome Sequencing

  • Next Generation Sequencing (NGS) of the whole genome was performed on two cases and two controls. This identified over 10,000 single-nucleotide variants (SNVs) and insertion or deletion mutations (indels) within the haplotype (a group of genes inherited from a single parent) associated with the disease.
  • A total of 17 SNVs and 5 indels were found to segregate (be inherited) with the disease and were located within or adjacent to genes.

SERPINB11 Gene

  • Among the genetic variants identified, an insertion mutation in the SERPINB11 gene was discovered that introduced a frameshift mutation, effectively create a premature stop codon in the genetic sequence.
  • It was found that expression of SERPINB11 was significantly reduced in affected ponies, while the frequency of the carrier variant for the disease was estimated at 14.8% among Connemara ponies.
  • The study concludes that this is the first time a variant in the SERPINB11 gene has been associated with a hoof wall-specific phenotype, hinting at a role of the gene in maintaining hoof wall structure.

Cite This Article

APA
Finno CJ, Stevens C, Young A, Affolter V, Joshi NA, Ramsay S, Bannasch DL. (2015). SERPINB11 frameshift variant associated with novel hoof specific phenotype in Connemara ponies. PLoS Genet, 11(4), e1005122. https://doi.org/10.1371/journal.pgen.1005122

Publication

PLoS genetics
ISSN: 1553-7404
NlmUniqueID: 101239074
Country: United States
Language: English
Volume: 11
Issue: 4
Pages: e1005122

Researcher Affiliations

Finno, Carrie J
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
Stevens, Carlynn
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
Young, Amy
  • Department of Animal Science, University of California Davis, Davis, California, United States of America.
Affolter, Verena
  • Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
Joshi, Nikhil A
  • Genome Center Bioinformatics Core, University of California Davis, Davis, California United States of America.
Ramsay, Sheila
  • Institute of Veterinary, Animal and Biomedical Sciences (IVABS) Massey University, Palmerston North, New Zealand.
Bannasch, Danika L
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.

MeSH Terms

  • Animals
  • Frameshift Mutation
  • Hoof and Claw / anatomy & histology
  • Horses / genetics
  • Phenotype
  • Polymorphism, Genetic
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Serpins / genetics
  • Serpins / metabolism

Grant Funding

  • K01 OD015134 / NIH HHS
  • L40 TR001136 / NCATS NIH HHS

Conflict of Interest Statement

The Regents of the University of California Davis have applied for a provisional patent application for the testing of this mutation in horses and ponies.

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