# Genetics and Pathobiology of Cutaneous Mosaic Disorders

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $570,288

## Abstract

Cutaneous mosaic disorders are severe, rare genetic skin disorders appearing in patterns due
to somatic mutation during embryonic development. The timing of mutation determines the
identity and extent of affected tissue, and given contributions of ectoderm (keratinocytes),
mesoderm (fibroblasts, cutaneous vessels), and neural crest (melanocytes) to the skin, one or
multiple cell types can be affected. We have found that consequences of such mutations can
be severe as in rapidly-growing, treatment-unresponsive congenital hemangiomas due to
GNA14 mutation, or severe osteomalacia in the cutaneous-skeletal hypophosphatemia
syndrome due to multi-lineage somatic activating RAS mutations. Next generation sequencing
has powered gene discovery in cutaneous mosaic disorders, and we have successfully
identified several novel genetic causes of these conditions. We now propose to expand our
cohort of well-phenotyped cutaneous mosaic disorders, to screen for mutations in potential
causative genes, and to employ exome sequencing in mutation-unknown subjects with reflex to
genome sequencing for unsolved cases to discover novel genetic causes. Included in this
cohort are proliferative/hamartomatous conditions including congenital fascial dystrophy, nevus
comedonicus, and congenital hemangiomas, as well as rare mosaic presentations of common
disorders including acne, psoriasis, lichen planus, and discoid lupus erythematosus, which
provide an opportunity to identify pathways relevant to autoimmunity and inflammation. We will
utilize patient-derived cells and tissue to interrogate the function of identified novel genes, and
will employ transgenic tissue equivalents to study and prove pathogenesis of identified
mutations when possible. For a limited number of compelling, novel genes previously
unrecognized to be relevant to cutaneous biology, we will employ mouse models including
knockout and CRISPR-generated knockin lines to prove pathogenesis of identified mutations
and to provide initial insights into disease pathobiology. These studies will continue to identify
molecular pathways central to the complex processes of epidermal differentiation, self-renewal,
and inflammation, and will provide critical context for future biologic studies and development of
novel therapeutics.

## Key facts

- **NIH application ID:** 10131574
- **Project number:** 5R01AR071491-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** KEITH A CHOATE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $570,288
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131574

## Citation

> US National Institutes of Health, RePORTER application 10131574, Genetics and Pathobiology of Cutaneous Mosaic Disorders (5R01AR071491-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10131574. Licensed CC0.

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