Categories: Integument (skin) phene

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2021

History: The phenotype has been termed hair shaft dysplasia or hair shaft dystrophy by different pathologists.

Molecular basis: Kiener et al. (2022) investigated two unrelated domestic shorthair cats with partial alopecia and bulbous swellings of the hair shafts. Based on the striking phenotype resembling lanceolate mice, the authors focused their analysis on DSG4 encoding desmoglein 4 as the top functional candidate gene. The authors "sequenced the genomes from both affected cats and compared the data of each affected cat to 61 control genomes. A search for private homozygous variants in the DSG4 candidate gene revealed independent frameshift variants in each case, c.76del or p.Ile26fsLeu*4 in case no. 1 and c.1777del or p.His593Thrfs*23 in case no. 2. DSG4 is a transmembrane glycoprotein located primarily in the extracellular part of desmosomes, a complex of adhesion molecules responsible for connecting the keratin intermediate filaments of neighbouring epithelial cells. Desmosomes are essential for normal hair shaft formation. Both identified DSG4 variants in the affected cats lead to premature stop codons and truncate major parts of the open-reading frame. We assume that this leads to a complete loss of DSG4 function, resulting in an incorrect formation of the desmosomes and causing the development of defective hair shafts." (Kiener et al., 2022).

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Rostaher et al. (2021) described the clinical and histopathological phenotype in two out of four affected siblings in a litter of domestic shorthair cats. "Both cats presented with extensive alopecia of the dorsal thorax, plantar and palmar surfaces of the limbs, convex pinnae and most of the face. The cats were multicoloured and neither had alopecia associated with a specific coat colour. In addition to the affected truncal hairs, the vibrissae were short and broken. Macroscopic evaluation of the skin surface revealed many short, broken hair shafts, some of which had club or lance-head shaped ends. In addition to the unremarkable general physical examination, the nails, teeth, eyes and skin texture were unaffected." (Rostaher et al., 2021) Figure 2 of Kiener et al. (2022) compared the phenotypes of the original litter identified by Rostaher et al. (2021) and an unrelated case with an independent DSG4 variant. All investigated cats shared similar clinical features comprising partial alopecia and the presence of characteristic lance-shaped hair tips.

Pathology: "Light and scanning electron microscopy of the hairs revealed lance- or spear-head shaped defects of the hair tip. Histological findings were swollen hair shafts, initially above the hair bulb matrix and later found in the distal parts of the telogen hair follicles, similar to those observed in Dsg4^lahJ Krt75^tm1Der mutant mice. Transmission electron microscopy of the hair shaft and hair follicles showed a loss in the normal structure of the guard hairs in the alopecic cats. There was a statistically significant decrease in sulfur content just below the defects in the hair shafts (trichothiodystrophy)." (Rostaher et al., 2021).

Breed: Domestic Shorthair.
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: