Categories: Pigmentation phene , Mortality / aging (incl. embryonic lethal) , Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 308300 (trait) , 300248 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0010631: incontinentia pigmenti

Mendelian trait/disorder: yes

Mode of inheritance: X-linked incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: Familial incontinentia pigmenti (IP) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males (for a summary of the human disorder, see Smahi et al., 2000). In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes, and central nervous system. The prominent skin signs occur in 4 classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation, and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. As noted in the MIM entry hyperlinked above, it is possible that the bovine disorder Streaked hairlessness (also known as Streaked hypotrichosis) (OMIA 000542-9913) is actually homologous to Incontinentia pigmenti.

Species-specific name: Incontinentia pigmenti

Species-specific symbol: IP

Species-specific description: Incontinentia pigmenti (IP) is an ectodermal dysplasia 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.

History: This disorder was first reported in horses by Towers et al. (2013).

Inheritance: IP is inherited as an X-chromosomal dominant trait. Males that are hemizyous for the defect die during pregnancy in utero in horses and are aborted. Thus, the typical IP phenotype can only be seen in heterozygous females.

Mapping: Pedigree analysis of a horse family segregating for IP clearly indicated the X-chromosomal dominant inheritance (Towers et al. 2013).

Molecular basis: After having established the X-chromosomal inheritance the genome of an affected crossbred mare was re-sequenced at 19x coverage (Towers et al. 2013). The analysis of the sequence data yielded 557 non-synonymous variants on the X-chromosome with respect to the genome reference sequence of an unaffected Thoroughbred mare. Exclusion of variants that were also present in the genome sequences of 44 control horses from 11 breeds resulted in a reduced list of 33 private non-synonymous X-chromosomal variants in the IP affected mare. By visual inspection of this list and based on the knowledge of the human condition the authors concluded that a nonsense variant in the IKBKG gene is the most likely causative variant for IP in the investigated horse family. The variant is c.184C>T and predicted to result in p.Arg62* (omia.variant:337). The same variant at the homologous position in the human IKBKG gene had been previously reported in a human IP patient. The variant also showed perfect co-segregation with IP in the horse family and was present in all 3 available cases (Towers et al. 2013).

Clinical features: Affected mares develop pruritic, exudative lesions soon after birth. These evolve into wart-like lesions and areas of alopecia. Occasionally, hair re-growth with a wooly appearance is observed. Affected horses also have streaks of darker and lighter coat coloration from birth resembling the brindled coat color. The cutaneous manifestations follow the lines of Blaschko. Other clinical symptoms include anomalies of tooth, hoof and ocular development (Towers et al. 2013).

Breeds: Quarter Horse (Horse) (VBO_0001057), Warmblood (Horse) (VBO_0017483).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: