Research Article: A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs

Date Published: January 25, 2017

Publisher: Public Library of Science

Author(s): Margret L. Casal, Ping Wang, Elizabeth A. Mauldin, Gloria Lin, Paula S. Henthorn, Claire Wade.


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.

Partial Text

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 hydrophobic SC regulates water movement into and out of the skin and protects the body from environmental, microbial, and chemical insults. The SC represents a unique evolutionary adaptation that allowed vertebrates to exist in a terrestrial environment. When defective, 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.

This paper characterizes a deleterious molecular defect in the NIPAL4 gene encoding ichthyin associated with ARCI in the ABD breed of dogs. A homozygous cytosine deletion in exon 6 of NIPAL4 was identified in all 40 ABDs affected with ARCI in this study. Obligate carriers (N = 21) were confirmed heterozygous for this variant. DNA samples from 800 ABDs were collected from the North America, Europe and Australia during 2008–2013 and genotyped. While the population tested was not a random population, and probably biased to inflate the incidence of the disease-associated allele, the allele frequency of this single base deletion was 22.4%, with 39.3% of all dogs tested being either carriers or affected. The bias can be explained by assuming that owners of relatives of known affected dogs were more likely to test their dogs than owners that were not aware of affected relatives of their dogs. Since the introduction of the NIPAL4 variant test, fewer numbers of affected dogs have been reported (MLC, unpublished data). It has allowed the breeders to retain dogs for breeding that have outstanding breed related qualities but are heterozygotes. Therefore, they can be mated with non-carriers without the fear of producing affected puppies while preserving desirable genes and thus, traits.




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