What is the human equivalent of Ichthyosis (Discovered in the American Bulldog; NIPAL4-related)?

OMIA links Ichthyosis (Discovered in the American Bulldog; NIPAL4-related) to its human counterpart in OMIM (OMIM 612281), the bridge to the deeper human-medicine literature for the same underlying biology.

Canine Mendelian disease record

Ichthyosis (Discovered in the American Bulldog; NIPAL4-related)

Q: How well studied is Ichthyosis (Discovered in the American Bulldog; NIPAL4-related) in dogs?

OMIA curates 5 peer-reviewed references for Ichthyosis (Discovered in the American Bulldog; NIPAL4-related). The full, linked citation list is on this page.

Ichthyosis (Discovered in the American Bulldog; NIPAL4-related). Autosomal recessive. Observed in 5 of 266 breeds tested in the Sniff Atlas, with measured carrier frequencies drawn from 242,665 dogs (Donner 2023). Per-dog phenotype outcome depends on penetrance, modifiers, and environment; the carrier frequencies below describe variant prevalence, not disease incidence.

OMIA identifier: OMIA:001980-9615
Inheritance: Autosomal recessive
Source dataset: Sniff Atlas v1.0.1 / DOI

The human connection

A model of human autosomal recessive congenital ichthyosis 6

This is the canine counterpart of autosomal recessive congenital ichthyosis 6 in people. That makes affected dogs a naturally-occurring model of the human disease, and it is part of why studying dogs moves medicine forward for everyone. It does not mean your dog has the human disease. It means the two share an underlying biology.

In people, the disease is described as: Any autosomal recessive congenital ichthyosis in which the cause of the disease is a mutation in the NIPAL4 gene.

In humans it is also called: ARCI6, autosomal recessive congenital ichthyosis type 6, ichthyosis, congenital, autosomal recessive 6.

MONDO:0012847 OMIM 612281

Mapped from OMIA via the human disease's OMIM entry to the Mondo Disease Ontology (Monarch Initiative, CC-BY 4.0). Sniff renders this as a model-of link; the canine disease remains the subject of this page.

About this disease

From OMIA's curated record

Documented in OMIA (Online Mendelian Inheritance in Animals). This describes the disease as recorded in the published literature, not a prediction for any individual dog. As of 2026-06-03.

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).

Molecular genetics

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.

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."

Human analog

OMIA links this condition to its human counterpart in OMIM (Mendelian Inheritance in Man), the place to read across to the deeper human literature for the same biology.

Disease · OMIM 612281 Gene · OMIM 609383

Source: OMIA (Nicholas, Tammen & the Sydney Informatics Hub), entry OMIA:001980-9615, doi:10.25910/2AMR-PV70 (CC-BY 4.0).

Signs & cross-references

How it presents

Catalogued in the Mondo disease ontology (the cross-species disease identity used by the Monarch Initiative) as autosomal recessive congenital ichthyosis 6 (MONDO:0012847).

Phenotype terms: Human Phenotype Ontology + Mammalian Phenotype Ontology; disease terms: Mondo (Monarch Initiative). Cross-references curated by OMIA (doi:10.25910/2AMR-PV70, CC-BY 4.0).

The evidence

Published references

The peer-reviewed papers behind this disease, curated by OMIA. Starred entries are OMIA-designated landmark papers.

Ichthyosis and hereditary cornification disorders in dogs. · Vet Dermatol · 2021 · PMID 34796560
NIPAL4 deletion identified in an American Bully with autosomal recessive congenital ichthyosis and response to topical therapy. · Vet Med Sci · 2019 · PMID 30741495
A defect in NIPAL4 is associated with autosomal recessive congenital ichthyosis in American bulldogs. · PLoS One · 2017 · PMID 28122049
Autosomal recessive congenital ichthyosis in American bulldogs is associated with NIPAL4 (ICHTHYIN) deficiency. · Vet Pathol · 2015 · PMID 25322746
Canine ichthyosis and related disorders of cornification. · Vet Clin North Am Small Anim Pract · 2013 · PMID 23182326

References curated by OMIA (Nicholas, Tammen & the Sydney Informatics Hub), doi:10.25910/2AMR-PV70 (CC-BY 4.0). Full list at the OMIA entry.

Predict a litter

Set each parent's status for Ichthyosis (Discovered in the American Bulldog; NIPAL4-related) and see the odds for their puppies. Single recessive variant, exact Mendelian math.

Parent A

Parent B

NNClear

NmCarrier

mmAffected

Clear25%

Carrier50%

Affected25%

These are the genetic odds for one known variant, not a promise: a real litter varies around them, and penetrance or other genes can change whether the condition ever appears. Use it to avoid pairing two carriers and to keep a line healthy, not to engineer a dog. Inheritance mode per OMIA.

Your breed

See what Ichthyosis (Discovered in the American Bulldog; NIPAL4-related) looks like in your dog's breed.

Carrier frequency by breed

Top 5 well-sampled breeds (n ≥ 50)

Maximum carrier frequency per breed across variants in the Donner 2023 cohort, with Wilson 95% confidence intervals. The list below is split into well-sampled breeds (n ≥ 50 tested) and small-sample breeds (n < 50, where the Wilson CI typically spans more than 20 percentage points and frequencies should not be compared directly to the well-sampled entries). Frequencies are population-level, not per-litter or per-line.

0%10%20%

Bulldog American9.1% · n 540

9.1%n 540

American Staffordshire Terrier0.20% · n 42,793

0.20%n 42,793

Bulldog Standard<0.1% · n 4,816

<0.1%n 4,816

Boxer<0.1% · n 4,557

<0.1%n 4,557

Labrador Retriever<0.1% · n 16,856

<0.1%n 16,856

n = 69,562 dogs · Donner et al. 2023 carrier-screening cohort · Sniff Atlas

Each bar is one well-sampled breed; the whisker is its Wilson 95% CI, and fainter bars have wider intervals. Frequencies are population-level, not per-litter. Carrier status for Ichthyosis (Discovered in the American Bulldog; NIPAL4-related) is measured; phenotype outcome depends on penetrance and modifiers.

▸ Full table with Wilson 95% confidence intervals

Breed	Carrier frequency	Wilson 95% CI	n tested
Bulldog American	9.1%	[6.9%, 11.8%]	540
American Staffordshire Terrier	0.20%	[0.2%, 0.3%]	42,793
Bulldog Standard	<0.1%	[0.0%, 0.2%]	4,816
Boxer	<0.1%	[0.0%, 0.1%]	4,557
Labrador Retriever	<0.1%	[0.0%, 0.0%]	16,856

261 additional breeds in the Donner 2023 cohort were tested but showed no carriers.

Penetrance

From genotype to phenotype

Carrier status is not the same as disease status. Penetrance is the fraction of at-risk dogs that develop the phenotype. The Donner 2023 S4 table tracks this for 1 variant(s) underlying this disease in the cohort.

At-risk dogs evaluated: 13
Phenotype confirmed: 13
Penetrance range: not yet quantifiable

Predicted disease relevance at the per-dog level is UNPROVEN. The carrier frequency is measured; phenotype outcome is governed by penetrance, environment, and modifier loci. Consult a veterinarian for clinical interpretation.

How to cite this record

If you use this record in published work, cite the Sniff Atlas (the published dataset that carries the breed-level carrier frequencies) and the upstream sources:

Sniff Atlas v1.0.1 for the per-breed carrier frequencies:
Gehring, M. (2026). Sniff Atlas v1.0.1. Zenodo. https://doi.org/10.5281/zenodo.20566358. CC-BY 4.0.
OMIA for the disease definition, inheritance, and gene assignment:
Nicholas, F. W., & Tammen, I. (2024). OMIA. Sydney Informatics Hub, The University of Sydney. https://doi.org/10.25910/2AMR-PV70. Entry: OMIA:001980-9615.
Donner et al. 2023 for the breed × variant carrier-frequency cohort:
Donner, J., Freyer, J., Davison, S., Anderson, H., Blades, M., Honkanen, L., et al. (2023). Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs. PLOS Genetics, 19(2), e1010651. https://doi.org/10.1371/journal.pgen.1010651.

Full citation formats (BibTeX, RIS, CITATION.cff) at sniff.world/cite.

Sniff Atlas v1.0.1, the source dataset for these frequencies.
Browse breeds, per-breed Mendelian profiles, including this disease in context.
OMIA entry OMIA:001980-9615, authoritative clinical reference.
About OMIA, the catalogue this record comes from, and how Sniff uses it.

Last updated June 20, 2026

Sources: Sniff Atlas v1.0.1 · OMIA OMIA:001980-9615 · Donner et al. 2023