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Keith Choate, MD, PhD

Associate Dean for Physician-Scientist Development and Professor of Dermatology, Pathology and Genetics; Associate Dean for Physician Scientist Development, Office of the Dean, School of Medicine; Director of Research, Dermatology

Contact Information

Keith Choate, MD, PhD

Mailing Address

  • PO Box 208059

    333 Cedar Street

    New Haven, CT, 06520-8059

    United States

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Yale Medicine

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Research Summary

We employ a comprehensive approach human genetic disorders, attempting to understand their clinical presenations by studying their genetics and pathobiology. Using genetic tools, we have identified new genetic causes of inherited disorders and we are actively studying how these genes function in health and disease.

Extensive Research Description

Genetics has informed our understanding of normal skin development and differentiation, largely due to the fact that mutations affecting the skin result in easily observed phenotypes. Genetic investigation has permitted us to identify a priori pathways previously unrecognized to be relevant to skin biology. These insights have been relevant to diagnosis, disease prevention, and development of novel therapeutics.

We have three ongoing projects in the lab:

1. Identification of novel genetic causes of inherited skin disorders including ichthyosis, inflammatory disorders and alopecia. We have developed one of the largest registries of kindreds with ichthyosis and have identified over 10 new genetic cause of this group of disorders – we employ cell, murine, and engineered tissue models to understand that biological basis of disease and the role of novel genes in disease pathobiology.

2. Identification of novel genetic causes of mosaic skin disorders including childhood malformations, vascular tumors, and linear presentations of inflammatory disorders. Mosaic disorders are the result of embryonic somatic mutation, with timing of mutation determining the extent of disease. Among other discoveries, we have systematically dissected pathways leading to development of aggressive infantile vascular tumors, identified novel causes of acne pathogenesis and hair follicle differentiation, and have identified Ras as a regulator of phosphate homeostasis. A new project is focused on linear manifestation of common inflammatory disorders such as lupus, psoriasis, and lichen planus with the expectation that investigation will identify novel pathways in cutaneous innate immunity.

3. Elucidation of mechanisms of revertant mosaicism in ichthyosis with confetti to enable therapeutic recombination in the skin. We have found that specific mutations in KRT1 and KRT10 cause ichthyosis with confetti which undergoes spontaneous self-correction via revertant mosaicism, resulting in hundreds to thousands of patches of normal skin. All spots arise from mitotic recombination, and have found that keratin mutations directly influence DNA damage and repair and that cellular competition favors reversion. We are employing forward genetics to identify the pathways relevant to recombination and competition.

Coauthors

Research Interests

Cell Biology; Genetics, Medical; Musculoskeletal Diseases; Human Genome Project; Skin and Connective Tissue Diseases

Public Health Interests

Cancer; Genetics, Genomics, Epigenetics; Child/Adolescent Health

Selected Publications

  • Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.Boyden LM, Vincent NG, Zhou J, Hu R, Craiglow BG, Bayliss SJ, Rosman IS, Lucky AW, Diaz LA, Goldsmith LA, Paller AS, Lifton RP, Baserga SJ, Choate KA. Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. American Journal Of Human Genetics 2017, 100:978-984.
  • Somatic Mutations in NEK9 Cause Nevus Comedonicus.Levinsohn JL, Sugarman JL, McNiff JM, Antaya RJ, Choate KA. Somatic Mutations in NEK9 Cause Nevus Comedonicus. American Journal Of Human Genetics 2016, 98:1030-1037.
  • GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.Lim YH, Bacchiocchi A, Qiu J, Straub R, Bruckner A, Bercovitch L, Narayan D, McNiff J, Ko C, Robinson-Bostom L, Antaya R, Halaban R, Choate KA. GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation. American Journal Of Human Genetics 2016, 99:443-50.
  • Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.Choate KA, Lu Y, Zhou J, Choi M, Elias PM, Farhi A, Nelson-Williams C, Crumrine D, Williams ML, Nopper AJ, Bree A, Milstone LM, Lifton RP. Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10. Science (New York, N.Y.) 2010, 330:94-7.
  • Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.Choate KA, Lu Y, Zhou J, Elias PM, Zaidi S, Paller AS, Farhi A, Nelson-Williams C, Crumrine D, Milstone LM, Lifton RP. Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti. The Journal Of Clinical Investigation 2015, 125:1703-7.
  • Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.Boyden LM, Craiglow BG, Zhou J, Hu R, Loring EC, Morel KD, Lauren CT, Lifton RP, Bilguvar K, Paller AS, Choate KA. Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia. The Journal Of Investigative Dermatology 2015, 135:1540-1547.
  • Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.Levinsohn JL, Tian LC, Boyden LM, McNiff JM, Narayan D, Loring ES, Yun D, Sugarman JL, Overton JD, Mane SM, Lifton RP, Paller AS, Wagner AM, Antaya RJ, Choate KA. Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. The Journal Of Investigative Dermatology 2013, 133:827-830.
  • Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi.Levinsohn JL, Teng J, Craiglow BG, Loring EC, Burrow TA, Mane SS, Overton JD, Lifton RP, McNiff JM, Lucky AW, Choate KA. Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi. The Journal Of Investigative Dermatology 2014, 134:1149-1152.
  • Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.Lim YH, Ovejero D, Sugarman JS, Deklotz CM, Maruri A, Eichenfield LF, Kelley PK, Jüppner H, Gottschalk M, Tifft CJ, Gafni RI, Boyce AM, Cowen EW, Bhattacharyya N, Guthrie LC, Gahl WA, Golas G, Loring EC, Overton JD, Mane SM, Lifton RP, Levy ML, Collins MT, Choate KA. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Human Molecular Genetics 2014, 23:397-407.
  • Somatic ATP2A2 mutation in a case of papular acantholytic dyskeratosis: mosaic Darier disease.Knopp EA, Saraceni C, Moss J, McNiff JM, Choate KA. Somatic ATP2A2 mutation in a case of papular acantholytic dyskeratosis: mosaic Darier disease. Journal Of Cutaneous Pathology 2015, 42:853-7.
  • Somatic V600E BRAF Mutation in Linear and Sporadic Syringocystadenoma Papilliferum.Levinsohn JL, Sugarman JL, Bilguvar K, McNiff JM, Choate KA. Somatic V600E BRAF Mutation in Linear and Sporadic Syringocystadenoma Papilliferum. The Journal Of Investigative Dermatology 2015, 135:2536-2538.
  • Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma.Lim YH, Douglas SR, Ko CJ, Antaya RJ, McNiff JM, Zhou J, Choate KA, Narayan D. Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma. The Journal Of Investigative Dermatology 2015, 135:1698-1700.
  • An incompletely penetrant novel mutation in COL7A1 causes epidermolysis bullosa pruriginosa and dominant dystrophic epidermolysis bullosa phenotypes in an extended kindred.Yang CS, Lu Y, Farhi A, Nelson-Williams C, Kashgarian M, Glusac EJ, Lifton RP, Antaya RJ, Choate KA. An incompletely penetrant novel mutation in COL7A1 causes epidermolysis bullosa pruriginosa and dominant dystrophic epidermolysis bullosa phenotypes in an extended kindred. Pediatric Dermatology 2012, 29:725-31.

Clinical Trials

ConditionsStudy Title
Diseases of the Endocrine SystemA Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis
Immune SystemStudy of Adult Patients Receiving DUPIXENT® for Atopic Dermatitis (AD) (PROSE)
Immune SystemRESET Trial - Part 1 (Followed by Reset Trial - Part 2) - A Phase 3 Trial in Subjects With Sjögren-Larsson Syndrome (SLS)
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