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

Casal, Margret L.; Wang, Ping; Mauldin, Elizabeth A.; Lin, Gloria H. Y.; Henthorn, Paula S.

doi:10.1371/journal.pone.0170708

Cited by 23 publications

(38 citation statements)

References 19 publications

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“…The NIPAL4 variant described in the American Bulldog has not yet been observed in any other breed (Casal et al . ).…”

Section: Discussionmentioning

confidence: 97%

“…; & Casal et al . ). Clinically, American Bulldog ichthyosis is described as an ARCI similar to human lamellar ichthyosis or congenital ichthyosiform erythroderma.…”

Section: Introductionmentioning

confidence: 97%

“…; & Casal et al . ). Affected American Bulldogs present a dishevelled pelage with generalized soft white scales; the glabrous skin of the abdomen presents a brown discoloration, slight erythema and diffusely adherent light brown scales.…”

Section: Introductionmentioning

confidence: 97%

“…; & Casal et al . ). Microscopic skin lesions include diffuse laminated to compact orthokeratotic hyperkeratosis with hypergranulosis and acanthosis.…”

Section: Introductionmentioning

confidence: 97%

“…In dogs, several forms of ichthyosis have been described and are currently subdivided into epidermolytic and nonepidermolytic based on light microscopy (Credille 2008). Several breed-specific causative variants have been identified such as: KRT10 in the Norfolk Terrier, causing epidermolytic ichthyosis; PNPLA1 in the Golden Retriever, TGM1 in the Jack Russel Terrier, SLC27A4 in the Great Dane, ASPRV1 in the German Shepherd and NIPAL4 in the American Bulldog causing different forms of nonepidermolytic ichthyosis (Credille et al 2009;Grall et al 2012;Metzger et al 2015;Bauer et al 2017;& Casal et al 2017). Clinically, American Bulldog ichthyosis is described as an ARCI similar to human lamellar ichthyosis or congenital ichthyosiform erythroderma.…”

Section: Introductionmentioning

confidence: 99%

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NIPAL4 deletion identified in an American Bully with autosomal recessive congenital ichthyosis and response to topical therapy

Briand

Cochet-Faivre

Reyes-Gomez

et al. 2019

Veterinary Medicine & Sci

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Ichthyoses represent a heterogeneous group of hereditary cornification disorders characterized by generalized scaling of the skin. An autosomal recessive congenital ichthyosis ( ARCI ) has been described in American Bulldogs and is caused by a variant in the NIPAL 4 gene encoding for the ICHTHYIN protein. So far, this variant has not been described in other breeds. A 1.5‐year‐old female pedigreed American Bully was referred for generalized scaling and bad coat quality since adoption at 8 weeks of age. Clinical examination, cytological and histopathological examination, and DNA testing were performed. Clinical examination revealed a generalized scaling; cytological evaluation using impression with acetate tapes showed a secondary Malassezia dermatitis. Histopathological examination revealed a moderate to marked, diffuse, compact orthokeratotic hyperkeratosis with the formation of large scales. Few Malassezia were observed in the stratum corneum associated with minimal mixed perivascular inflammation and moderate epidermal hyperplasia. DNA testing of the dog revealed that he carries two defective alleles of the NIPAL 4 gene previously described in the American Bulldog. We performed a commercially available breed detection test which, although not specifically testing for “American Bully” signatures, revealed a high probability of American Bulldog DNA signature within the past three generations. Topical treatment using a combination of keratolytic and keratomodulator shampoo, emollient and moisturizers spray and antimicrobial wipes achieved a marked clinical improvement after only 1 month. Continuous topical treatment was necessary to maintain clinical improvement. To the authors’ knowledge, this is the first description of the deleterious NIPAL 4 variant in an American Bully as well as the first description of clinical management and follow‐up of ARCI in this breed.

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“…The NIPAL4 variant described in the American Bulldog has not yet been observed in any other breed (Casal et al . ).…”

Section: Discussionmentioning

confidence: 97%

“…; & Casal et al . ). Clinically, American Bulldog ichthyosis is described as an ARCI similar to human lamellar ichthyosis or congenital ichthyosiform erythroderma.…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

“…; & Casal et al . ). Microscopic skin lesions include diffuse laminated to compact orthokeratotic hyperkeratosis with hypergranulosis and acanthosis.…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

NIPAL4 deletion identified in an American Bully with autosomal recessive congenital ichthyosis and response to topical therapy

Briand

Cochet-Faivre

Reyes-Gomez

et al. 2019

Veterinary Medicine & Sci

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A frameshift insertion in FA2H causes a recessively inherited form of ichthyosis congenita in Chianina cattle

et al. 2021

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The aim of this study was to characterize the phenotype and to identify the genetic etiology of a syndromic form of ichthyosis congenita (IC) observed in Italian Chianina cattle and to estimate the prevalence of the deleterious allele in the population. Sporadic occurrence of different forms of ichthyosis including IC have been previously reported in cattle. However, so far, no causative genetic variant has been found for bovine IC. Nine affected cattle presenting congenital xerosis, hyperkeratosis and scaling of the skin as well as urolithiasis and cystitis associated with retarded growth were examined. Skin histopathology revealed a severe, diffuse orthokeratotic hyperkeratosis with mild to moderate epidermal hyperplasia. The pedigree records indicated a monogenic recessive trait. Homozygosity mapping and whole-genome sequencing allowed the identification of a homozygous frameshift 1 bp insertion in the FA2H gene (c.9dupC; p.Ala4ArgfsTer142) located in a 1.92 Mb shared identical-by-descent region on chromosome 18 present in all cases, while the parents were heterozygous as expected for obligate carriers. These findings enable the selection against this sub-lethal allele showing an estimated frequency of ~ 7.5% in Chianina top sires. A sporadic incidence of mild clinical signs in the skin of heterozygous carriers was observed. So far, pathogenic variants affecting the encoded fatty acid 2-hydroxylase catalyzing the synthesis of 2-hydroxysphingolipids have been associated with myelin disorders. In conclusion, this study represents the first report of an FA2H-related autosomal recessive inherited skin disorder in a mammalian species and adds FA2H to the list of candidate genes for ichthyosis in humans and animals. Furthermore, this study provides a DNA-based diagnostic test that enables selection against the identified pathogenic variant in the Chianina cattle population. However, functional studies are needed to better understand the expression of FA2H in IC-affected Chianina cattle.

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Cellular and Metabolic Basis for the Ichthyotic Phenotype in NIPAL4 (Ichthyin)–Deficient Canines

Mauldin

Crumrine

Casal

et al. 2018

The American Journal of Pathology

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Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.

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

Cited by 23 publications

References 19 publications

NIPAL4 deletion identified in an American Bully with autosomal recessive congenital ichthyosis and response to topical therapy

NIPAL4 deletion identified in an American Bully with autosomal recessive congenital ichthyosis and response to topical therapy

A frameshift insertion in FA2H causes a recessively inherited form of ichthyosis congenita in Chianina cattle

Cellular and Metabolic Basis for the Ichthyotic Phenotype in NIPAL4 (Ichthyin)–Deficient Canines

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