Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612281 (trait) , 609383 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0012847: autosomal recessive congenital ichthyosis 6

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2017

Species-specific name: autosomal recessive congenital ichthyosis

Species-specific symbol: ARCI

Mapping: Linkage analysis with microsatellite markers derived from likely candidate genes demonstrated linkage of the ichthyosis phenotype with the NIPAL4 gene (Mauldin et al. 2015).

Molecular basis: Immunohistochemistry on skin biospies of affected dogs demonstrated a lack of NIPAL4 (also termed ichthyin) protein expression (Mauldin et al. 2015). The authors identified a 338 bp SINE insertion upstream of the NIPAL4 gene in affected American Bulldogs, which represents a strongly associated marker, but not the causative variant (Margret Casal, personal communication). By sequencing "six exons of NIPAL4 gene from DNA obtained from an ARCI affected dog, and its clinically healthy parents and littermates", Casal et al. (2017) identified "a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC_06586.3 g.52737379del), the 157th base (cytosine) in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin) protein of 248 amino acids instead of the wild-type length of 404." Briand et al. (2019) reported the same likely causal variant in an affected American Bully.

Clinical features: The gross phenotype was manifest as a disheveled pelage shortly after birth, generalized scaling, and adherent brown scale with erythema of the abdominal skin (Mauldin et al. 2015).

Pathology: Affected dogs exhibited diffuse laminated to compact orthokeratotic hyperkeratosis with hypergranulosis and mild acanthosis. The epidermis had a prominent granular layer, and multifocal granular layer keratinocytes displayed a perinuclear clear space. Malassezia could be found within the corneal layer in at least one sample in approximately 60% of cases. The yeast were typically present without an inflammatory response. Ultrastructurally, the epidermis showed discontinuous lipid bilayers, unprocessed lipid within corneocytes, and abnormal lamellar bodies (Mauldin et al. 2015).

Prevalence: As reported by Casal et al. (2017), "Obligate carriers were confirmed to be heterozygous for this variant, and 150 clinically non-affected dogs of other breeds were homozygous for the wild-type gene. Among 800 American bulldogs tested, 34% of clinically healthy dogs were discovered to be heterozygous for the defective allele."

Breeds: American Bulldog (Dog) (VBO_0200034), American Bully (Dog) (VBO_0200036).
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: