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.

Figure 1. Phenotype of an affected horse.

Brindled pigmentation and patches of hairless skin are visible. The hairless skin probably represents scarring alopecia following the different stages of skin lesions described. The patterns of hyperpigmentation and the skin alterations follow the lines of Blaschko. The depicted horse corresponds to animal III-10 in the pedigree shown in Figure 2.

Figure 2. Pedigree of the horse family presented in this study.

The affected animals are shown as filled symbols. Non-affected animals are shown with open symbols. Males are shown as squares and females as circles; aborted foals (sex unknown) are shown as small black circles. The whole genome re-sequencing experiment was performed with DNA from animal II-8. The horse II-2 was killed in an accident and III-2 was born dead. Both deceased animals showed clear signs of IP.

Figure 3. Sanger sequencing of the IKBKG:c.184C>T variant.

Electropherograms of a homozygous wildtype and a heterozygous mare are shown. The reading frame and position of the nonsense variant are indicated. The variant is chrX:122,833,887C>T with respect to the EquCab 2 genome reference sequence.