SERPINB11 Frameshift Variant Associated with Novel Hoof Specific Phenotype in Connemara Ponies

Carrie J Finno, Carlynn Stevens, Amy Young, Verena K Affolter, Nikhil A. Joshi, Sheila Ramsay, Danika L Bannasch

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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 (n<inf>cases</inf> = 15, n<inf>controls</inf> = 24). Population stratification (λ = 1.48) was successfully improved by removing outliers (n<inf>controls</inf> = 7) identified on a multidimensional scaling plot. A genome-wide significant association was detected on chromosome 8 (p<inf>raw</inf> = 1.37x10<sup>-10</sup>, p<inf>genome</inf> = 1.92x10<sup>-5</sup>). 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 (n<inf>cases</inf> = 23, n<inf>controls</inf> = 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 (n<inf>cases</inf> = 4, n<inf>controls</inf> = 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.

Original languageEnglish (US)
Article numbere1005122
JournalPLoS Genetics
Issue number4
StatePublished - Apr 1 2015

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)


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