Categories: Integument (skin) phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 139350 (gene) , 113800 (trait) , 146590 (trait) , 607602 (trait) , 607654 (trait) , 144200 (trait) , 600962 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific name: Non-epidermolytic ichthyosis

Molecular basis: Affolter et al. (2022) investigated a single affected dog and its parents. The authors performed whole genome trio sequencing and focussed their search on 36 functional candidate genes for ichthyosis. An initial search for private protein-changing variants in the affected dog against 793 publicly available control genomes (excluding the parents) revealed 2 heterozygous candidate variants. Further analysis of the parents' genomes demonstrated that one of these variants in the affected offspring was the result of a de novo mutation event. The identified variant was a 3 bp deletion in the first exon of the KRT1 gene encoding keratin 1 (NM_001003392.1:c.567_569del). This inframe deletion is predicted to remove a highly conserved asparagine from the coil 1A domain of keratin 1, NP_001003392.1:p.(Asn190del). The coil 1A domain of kertain 1 is involved in the heterodimerization with keratin 10 and forms a part of the central rod domain of the KRT1/KRT10 dimer. Immunohistochemistry demonstrated KRT1 protein expression in the epidermis of the affected dog at a comparable level to an unaffected control. The authors hypothesized that the mutant allele might interfere with the formation of the KRT1/KRT10 heterodimeric keratin filaments. Missense variants affecting the homologous amino acid residue have been shown to cause a non-epidermolytic ichthyosis in human patients.

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

Clinical features: Affolter et al. 2022: "A 3-months old male Chinese shar-pei was presented for scaly skin and reduced overall body growth when compared with his 3 littermates ... At the time of presentation severe generalized scaling and alopecia was noted, with scaling most prominent on the head, neck, abdomen, legs, axillary folds and paws. Prominent follicular fronds accompanied surface scaling. The paw pads appeared deformed and hyperkeratotic. Pruritus was not observed. The left eye had an entropium. Skin scrapings for Demodex mites were negative. Skin cytology revealed numerous yeast organisms."

Pathology: Affolter et al. 2022: "Biopsies from all three locations revealed severe hyperkeratosis, characterized by prominent keratin lamellae overlaying a marked compact layer of keratin. The epidermis was markedly acanthotic and most infundibular regions were markedly dilated resulting in narrowing of the interfollicular epidermis. The follicular lumina were filled with keratin and the infundibular epithelium was hyperplastic. Some perinuclear clearing was most evident in the prominent granular layer with irregularly sized keratohyalin. Dispersed mast cells and some plasma cells and neutrophils were present in the superficial dermis and the sebaceous glands were prominent. Several small neutrophilic crusts with some cocci were noted entrapped within the thick keratin layer. In the sample from the shoulder some follicles contained neutrophils in their lumina and the epidermis was covered by parakeratosis. Superficial yeast organisms were not observed in sections stained with periodic acid-Schiff stain. Many hair follicles and remaining hair shafts contained clumped melanin. The following morphologic diagnoses were made: 1) severe acanthosis and superficial and follicular hyperkeratosis suggestive of a cornification disturbance and 2) multifocal neutrophilic pustular dermatitis and neutrophilic luminal folliculitis and 3) melanin pigment clumping indicating dilute hair coat color. The latter was considered an expected incidental finding as the dog had a d1/d2 genotype at the MLPH gene and was born out of two clinically inconspicuous dilute-colored parents. Given the overwhelming features of follicular and superficial hyperkeratosis, a hereditary cornification disorder consistent with ichthyosis was considered. Pustules and superficial folliculitis indicated a secondary pyoderma, which, based on skin cytology, was accompanied by a superficial yeast infection."

Prevalence: Affolter et al. (2022) reported on a single affected dog born out of unaffected parents. The ichthyosis phenotype was the result of a de novo mutation event. Therefore, the studied dog most likely represented a unique case.

Breed: Chinese Shar-Pei (Dog) (VBO_0200351).
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: