Abstract
Autosomal recessive congenital ichthyosis in the American bulldog is characterized by generalized scaling and erythema with adherent scale on the glabrous skin. We had previously linked this disorder to NIPAL4, which encodes the protein ichthyin. Sequencing of NIPAL4 revealed 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. 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. More importantly, the development of this canine model of autosomal recessive congenital ichthyosis will provide insight into the development of new treatments across species.
Highlights
Autosomal recessive congenital ichthyosis (ARCI, Online Mendelian Inheritance in Man [OMIM] #612281) is a rare skin disorder caused by defective formation of the skin barrier— the stratum corneum (SC)
We present here the discovery of a disease-associated variant in NIPAL4 that establishes ARCI in American Bulldogs (ABDs) as an animal model that can be used to better understand the disease process in humans and to develop therapies for this scaling disorder
All ARCI affected dogs were diagnosed by clinical evaluation and histopathologic examination as described [6]
Summary
Autosomal recessive congenital ichthyosis (ARCI, Online Mendelian Inheritance in Man [OMIM] #612281) is a rare skin disorder caused by defective formation of the skin barrier— the stratum corneum (SC). The clinical phenotype (e.g. scaling) reflects the body’s attempt to restore hydrophobicity and repair the flawed skin barrier. ARCIs are monogenetic disorders caused by variants in the genes that encode a wide array of molecules, including enzymes, structural proteins, and lipids, involved in the formation of the SC. ARCI represents a group of rare inherited skin disorders characterized by excessive scaling. The incidence of congenital ichthyosis is 5–10 per 100,000 births in the United States [1]. This disorder usually presents at an early age and continues to affect the patients
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