Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 300945 (gene) , 300946 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: X-linked incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific name: Streaked hairlessness

History: This disorder was reported in Holstein-Friesian cattle by Eldridge and Atkeson (1953). At that time the molecular genetics was not investigated. Murgiano et al. (2015) observed a very similar phenotype in Italian Pezzata Rossa cattle and identified a TSR2 splice site variant as most likely causative variant.

Inheritance: Eldridge and Atkeson (1953) reported extensive Holstein-Friesian data strongly suggestive of "a semi-dominant, sex-linked lethal". Murgiano et al. (2015) confirmed an X-linked semi-dominant mode of inheritance in Pezzata Rossa cattle.

Mapping: As noted by Eldridge and Atkeson (1953), this is "the first character to be reported in dairy cattle for which the causative gene can be quite definitely located on a specific chromosome" (because of their data supporting X-linked inheritance) and consequently "the gene for streaked hairlessness becomes a marker for one linkage group, and thus is the first step towards building a chromosome map for cattle".

Molecular basis: Murgiano et al. (2015) investigated a family of Pezzata Rossa cattle with 4 affected cows. The pedigree was suggestive of X-linked semi-dominant inheritance with lethality in hemizygous mutant males. Two autosomal segments on chromosome 7 and 14 also showed positive LOD scores in a linkage analysis and could not definitively be excluded. Whole genome sequencing of one affected cow at 28x coverage and comparison to the 1000 bull genomes' sequence data identified two private coding variants in the critical intervals on BTA 7, 14, and X. These variants were a missense variant in ERCC6L and a splice site variant in TSR2. Expression analysis in mouse embryos demonstrated specific expression of TSR2 in developing hair-follicles whereas ERCC6L was not found to be expressed in hair follicles. Therefore, the authors concluded that the TSR2 variant (c.441+226A>G), which changed the conserved 3'-splice site of intron 4 from AG into GG, is the most likely causative variant. The authors analyzed the TSR2 transcripts in biopsies from lesional (hairless) and non-lesional skin areas from affected cows. The splice site variant leads to aberrant splicing with either retention of intron 4 or to a lesser degree activiation of a cryptic splice site within exon 5. The proportion of mutant transcripts was much higher in hairless skin compared to hairless skin, which is most likely due to a higher percentage of active X-chromosomes with the mutant allele. The transcript analysis thus provided very strong support for the causality of the TSR2 variant.

Clinical features: Murgiano et al. (2015) reported hairless lesions following the lines of Blaschko in affected Pezzata Rossa cattle. The hairless streaks were present from birth, varied in their extent and size in the different animals and consistently followed a vertical pattern. Hairless streaks were present bilaterally along both sides of the animals. Their V-shaped symmetrical convergence at the level of the back resulted in a fishbone-like pattern. Hairless streaks were also present on the head. The skin of the udder presented diffuse non-streaked hypotrichosis. The lesions occurred without any association to the coat color, both pigmented and unpigmented areas being affected. Apart from the hairlessness, the skin of the affected areas was smooth, of normal color and without any crusts. No macroscopic intermediate aspect was present between the affected area and the surrounding skin. No abnormal cutaneous pain sensations by pressure, pricking or pinching stimuli, were observed at the level of the hairless areas as compared to the haired skin. Pruritus was also not apparent. The lesions remained practically unchanged during a three-year observation period, and no sign of hair regrowth was observed. No alteration in the production of milk was reported but, with respect to the cows’ fertility, the owner reported that one affected cow failed to conceive for five successive inseminations, which might possibly have been due to embryonic lethality in male hemizygous mutant embryos.

Pathology: Murgiano et al. (2015) reported that hair follicles in biopsies from the haired skin were normally distributed, and size and shape were comparable with hair follicles in skin biopsies from non-affected cows. In the skin biopsies from the hairless sites, the vast majority of the hair follicles and sebaceous glands were missing whereas the sweat glands, their ducts and the arrector pili muscles were present. Dysplastic or miniaturized hair bulbs or remnant fibrous sheaths surrounding the bulb were occasionally present. In addition, remnants of infundibula were rarely seen. In the biopsies from the haired-hairless border, a mixture of normal hair follicles and dysplastic infundibuli were present. The dysplastic infundibula were smaller than those of normal hair follicles, had an irregular outer contour and were often associated with the sebaceous glands and the ducts of the sweat glands.

Breeds: Holstein Friesian (Cattle) (VBO_0000239), Pezzata Rossa Italiana, Italy (Cattle) (VBO_0004147).
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: