# Genetics and Pathobiology of Disorders of Keratinization

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $522,931

## Abstract

PROJECT SUMMARY:
Disorders of keratinization (DOK) are severe, rare genetic skin disorders in which the central
barrier function of the skin is disrupted and a compensatory pathway of hyper-proliferation is
activated in either a localized area or throughout the entire skin surface. This results in a grossly
compromised epidermis that fails to adequately protect against bacterial, chemical, and
mechanical assault or to prevent transepidermal water loss. In early life, the consequences of
these disorders can be life-threatening, with increased susceptibility to infection due to blistering
and fissures, dramatically increased metabolic demands due to evaporative heat loss and
increased epidermal turnover rate, and various associated comorbid conditions and systemic
abnormalities which can persist throughout life. We and others have identified over 70 diverse
genes for these disorders, yet clinical experience and our data show that these genes explain
only a portion of heritability for DOK, which demonstrate marked locus and phenotypic
heterogeneity, with greater than 15% of subjects without mutation in known genes. In the last
funding period, we identified five new genes for DOK, provided evidence for phenotypic
expansion in two others, and identified a novel pathogenesis-directed therapy for one disorder.
We now propose to expand our large cohort of well-phenotyped DOK kindreds, to screen for
mutations in known causative genes, and to employ exome and genome sequencing in those
subjects without mutation in known DOK genes to discover novel genetic causes of these
disorders. We will employ patient-derived cells and tissue to interrogate the function of
identified novel genes, and will generate transgenic skin equivalents to study and prove
pathogenesis of identified mutations. For a limited number of novel genes not previously
implicated in DOK, we will generate mouse models using CRISPR technology to further
examine the effect of identified mutations on cutaneous function. These studies will continue to
identify molecular pathways central to the complex processes of epidermal differentiation and
self-renewal, and will provide critical context for more detailed future biologic studies.

## Key facts

- **NIH application ID:** 10371176
- **Project number:** 5R01AR068392-07
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** KEITH A CHOATE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $522,931
- **Award type:** 5
- **Project period:** 2015-08-03 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371176

## Citation

> US National Institutes of Health, RePORTER application 10371176, Genetics and Pathobiology of Disorders of Keratinization (5R01AR068392-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371176. Licensed CC0.

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