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

Carrie J Finno,Sheila Ramsay,Carlynn Stevens,Danika L Bannasch,Nikhil A Joshi,Amy Young,Verena Affolter,Gregory S Barsh

doi:10.1371/journal.pgen.1005122

Carrie J Finno, Sheila Ramsay + Show 6 more

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https://doi.org/10.1371/journal.pgen.1005122

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Journal: PLoS Genetics	Publication Date: Apr 13, 2015
Citations: 51	License type: CC BY 4.0

Affiliation: University of California, Davis, Massey University

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.

Highlights

Many of the signaling molecules involved in patterning ectodermal derivatives, such as teeth and hair, are involved in organizing mammalian distal limb appendages, including nails, claws and hooves [1]
This study describes an inherited disorder, termed Hoof Wall Separation Disease (HWSD), characterized by separation and breaking of the dorsal hoof wall in the Connemara pony
Distal extremity radiographs of both front feet and the dental arcade revealed no abnormalities

Summary

Introduction

Many of the signaling molecules involved in patterning ectodermal derivatives, such as teeth and hair, are involved in organizing mammalian distal limb appendages, including nails, claws and hooves [1]. Perissodactyla (odd-toed ungulates) are a diverse group of mammals that include the horse, zebra and donkey. These animals bear their weight almost entirely on the third toe. Raising the heel and digits off the ground increased the number of joints that move the limbs forward and thereby increased the rate of stride. These modifications substantially increase the potential speed and acceleration of these animals, extensive structural integrity of the hoof is required to support all of the body weight. Ground reaction forces increase at various phases of the gait, resulting in additional force applied to each hoof [2]

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