A Nonsense Mutation in the IKBKG Gene in Mares with Incontinentia Pigmenti

Abstract

Ectodermal dysplasias (EDs) are a large and heterogeneous group of hereditary disorders characterized by abnormalities in structures of ectodermal origin. Incontinentia pigmenti (IP) is an ED characterized by skin lesions evolving over time, as well as dental, nail, and ocular abnormalities. Due to X-linked dominant inheritance IP symptoms can only be seen in female individuals while affected males die during development in utero. We observed a family of horses, in which several mares developed signs of a skin disorder reminiscent of human IP. Cutaneous manifestations in affected horses included the development of pruritic, exudative lesions soon after birth. These developed into wart-like lesions and areas of alopecia with occasional wooly hair re-growth. Affected horses also had streaks of darker and lighter coat coloration from birth. The observation that only females were affected together with a high number of spontaneous abortions suggested an X-linked dominant mechanism of transmission. Using next generation sequencing we sequenced the whole genome of one affected mare. We analyzed the sequence data for non-synonymous variants in candidate genes and found a heterozygous nonsense variant in the X-chromosomal IKBKG gene (c.184C>T; p.Arg62*). Mutations in IKBKG were previously reported to cause IP in humans and the homologous p.Arg62* variant has already been observed in a human IP patient. The comparative data thus strongly suggest that this is also the causative variant for the observed IP in horses. To our knowledge this is the first large animal model for IP.

Imputation of sequence level genotypes in the Franches-Montagnes horse breed

“…We suspect that SNPs on this chromosome may have incorrect positions in the reference genome EquCab2.0 or contain errors in sequencing calls, since this chromosome also showed a low concordance between SNP-chip- and sequence-derived genotypes. Imperfect concordance between NGS data and EquCab2.0 is not a completely unknown phenomenon [ 38 ].…”

A Large Deletion in the NSDHL Gene in Labrador Retrievers with a Congenital Cornification Disorder

“…Skin lesions following Blaschko’s lines in heterozygous females are also known in animals with X-linked heritable phenotypes, for example, incontinentia pigmenti and brindle 1 in horses ( Towers et al 2013 ; Murgiano et al 2016 ), streaked hairlessness in cattle ( Murgiano et al 2015 ), or X-linked hypohidrotic ectodermal dysplasia in dogs ( Casal et al 1997 ).…”

Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation

“…Several forms of inherited alopecia have been described in domestic animal species (OMIA 001702–9913, OMIA 001702–9615, OMIA 001702–9796, OMIA 001702–9685, OMIA 001702–9825, OMIA 000031–9615, OMIA 000030–9685, OMIA 000030–9031, OMIA 000030–9940) [ 8 ], including hairlessness and X-linked phenotypes (OMIA 000543–9913) [ 9 , 10 , 11 ]. Our group has recently reported a family of horses in which females developed signs of a skin disorder reminiscent of human incontinentia pigmenti (OMIA 001899–9796) [ 10 ]. Notably, the affected horses showed congenital streaks of varying coat color which followed the lines of Blaschko, and a causative nonsense mutation was found in the X-chromosomal IKBKG gene [ 10 ].…”

“…Our group has recently reported a family of horses in which females developed signs of a skin disorder reminiscent of human incontinentia pigmenti (OMIA 001899–9796) [ 10 ]. Notably, the affected horses showed congenital streaks of varying coat color which followed the lines of Blaschko, and a causative nonsense mutation was found in the X-chromosomal IKBKG gene [ 10 ]. In general, the dissection of naturally occurring spontaneous mutations in domestic animals can lead to important insights into developmental genetics, as has been shown for hairless dogs carrying a FOXI3 mutation (OMIA 000323–9615) [ 12 ].…”