Date of Award

January 2019

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Keith A. Choate

Abstract

The ichthyoses are a heterogeneous group of skin diseases characterized by localized and/or generalized scaling. Other common manifestations include palmoplantar keratoderma, erythroderma, recurrent infections, and hypohidrosis. Abnormal barrier function is a cardinal feature of the ichthyoses, which results in compensatory hyperproliferation and transepidermal water loss. Barrier function is maintained primarily by the stratum corneum, which is composed of cornified cells surrounded by a corneocyte lipid envelope and intercellular lipid layers. The lipid components are comprised primarily by ceramides. Human genetics has advanced our understanding of the role of the epidermal lipid barrier, with a series of discoveries in animals and humans revealing mutations in novel genes causing disorders of keratinization. Recently, next-generation sequencing has further expanded our knowledge, identifying novel mutations that disrupt the ceramide pathway and result in disorders of keratinization. This review focuses on new findings in ichthyoses. We have recruited a cohort of over 1,000 comprehensively phenotyped DOK kindreds and are employing a tiered approach whereby cases are screened for mutations in 51 commonly causative genes, followed by whole exome sequencing to identify mutations in other known DOK genes and for novel gene discovery. Strategies include sequencing of parent-child trios to identify de novo mutations, and sequencing of paired genomic and affected tissue DNA samples when somatic mosaicism is suspected. We have identified a number of new genes for these disorders which inform our understanding of epithelial biology.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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