Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions

Lihi Atzmony, Theodore D. Zaki, Richard J. Antaya, Keith A. Choate*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Appearance of mosaic disorders in thin Blaschko lines suggests that somatic mutations in keratinocyte precursors underlie their pathogenesis. Germline heterozygous mutations in POFUT1 gene cause Dowling–Degos disease (DDD), a skin disease that features flexural reticulated hyperpigmentation and follicular-based lesions. POFUT1 mosaicism has not been described to date. Here, we describe a 9-year-old female with segmental hyper- and hypopigmented patches with overlying eczematous plaques and follicular papules. Employing paired whole exome sequencing of saliva and keratinocytes isolated from affected skin, we found a novel germline heterozygous POFUT1 deletion causing frameshift and premature codon termination and somatic copy-neutral loss of heterozygosity on chromosome 20 encompassing POFUT1. Expression levels of POFUT1 as well as other key regulators of the notch signaling pathway—NOTCH1, NOTCH2, and HES1—were reduced in affected keratinocytes compared with normal keratinocytes. Our findings provide the first evidence of POFUT1 postzygotic mutation and a phenotypic expansion of POFUT1 loss of function mutations. We show that a recessive loss of function mutation in POFUT1 produces a distinct clinical presentation with features (e.g., dermatitis) that are absent in the generalized form of DDD. This study demonstrates how analysis of mosaic disorders can reveal unexpected phenotypes for known genes.

Original languageEnglish
Pages (from-to)2469-2473
Number of pages5
JournalAmerican Journal of Medical Genetics, Part A
Volume179
Issue number12
DOIs
StatePublished - 1 Dec 2019

Funding

FundersFunder number
Davidoff Foundation
National Institutes of HealthWe
Yale University
National Institutes of Health
National Human Genome Research InstituteU54HG006504
National Institute of Arthritis and Musculoskeletal and Skin DiseasesR01 AR071491

    Keywords

    • Dowling–Degos disease
    • Notch signaling
    • POFUT1
    • genetics
    • mosaicism
    • pigmentation

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