Categories: Integument (skin) phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 190320 (trait) , 600525 (gene)

Links to MONDO diseases:

• MONDO:0008592: tricho-dento-osseous syndrome

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2017

Species-specific description: In a remarkable indication of the power of modern genomic tools, Hofstetter et al. (2017) reported a novel form of curly coat in a single Brown Swiss calf, the offspring of two normal-coated parents. By whole-genome sequencing of the calf and its sire and dam, followed by informed interrogation of the sequence data (as described below), these authors were able to identify a likely causal variant in a gene which, when mutated in humans, gives rise to a similar phenotype. Thus was a new animal model of a human disorder identified (see "Possible human homologue" above)

Inheritance: As reported by Hofstetter et al. (2017), the absence of the variant in both parents strongly suggests that the variant is a de novo dominant mutation. And the mutated gene, DLX3, is located on chromosome BTA19. Hence, even without pedigree data, it is reasonable to conclude that the trait is autosomal dominant.

Molecular basis: Hofstetter et al. (2017): "Genome-wide filtering for sequence variants in the whole genome that were present heterozygous only in the affected calf and homozygous wild-type (WT) in the genomes of both parents, resulted in 276 variants representing putative de novo sequence variants (Table S1). Out of these 276 variants, only a single 10 bp insertion on chromosome 19 (g.37298375_37298376insGGAGCACAGG) was located in a protein coding gene, namely in exon 3 of the bovine distal-less homeobox gene (DLX3) leading to a frameshift. . . . The mutation was predicted to produce a frameshift downstream the homeobox encoding region of the DLX3 mRNA (NM_001081622: c.584_585insGGAGCACAGG; NP_001075091: p.Ser198ArgfsTer99) resulting in a mutant protein of 296 residues. In comparison to the normal 287 amino acid-long DLX3 protein, the C-terminal transactivation domain of the WT protein is replaced by a 99 peptide with no similarities to known proteins".

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

Clinical features: Hofstetter et al. (2017): "Examination revealed a dull tousled hair coat with mild hypotrichosis of the ventral neck and legs (Figure 1a,b). The coat colour was typical for this breed. The hair shafts were not obviously fragile. The eyelashes were curly on both sides (Figure 1c). The concave and convex aspects of the pinnae were hypotrichotic (Figure 1d). The skin was dry and covered with fine scale. The incisor teeth were erupted and aligned correctly, and had a slight brown discolouration (Figure S1). Trichograms demonstrated irregular shaped hair shafts characterized by multiple indentations of the cuticle, cortex and medulla (Figure S2). Clinical examination was otherwise unremarkable. A complete blood count and biochemical analysis was unremarkable."

Pathology: Hofstetter et al. (2017): "Histological examination of skin biopsies demonstrated follicular dysplasia characterized by large vacuoles within the Henle and Huxley layer of the suprabulbar region of the hair follicles, an irregular thickness of the cornified inner root sheath and severely irregular contour of the hair shafts"

Breed: Brown Swiss (Cattle) (VBO_0000166).
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: