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SHR Neuro Cancer Cardio Lipid Metab Microb

Hörer, S; Marrakchi, S; Radner, FPW; Zolles, G; Heinz, L; Eichmann, TO; Has, C; Salavei, P; Mahfoudh, N; Turki, H; Zimmer, AD; Fischer, J.
A Monoallelic Two-Hit Mechanism in PLCD1 Explains the Genetic Pathogenesis of Hereditary Trichilemmal Cyst Formation.
J Invest Dermatol. 2019; 139(10): 2154-2163.e5. Doi: 10.1016/j.jid.2019.04.015
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Co-authors Med Uni Graz: Eichmann Thomas
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Abstract:: Trichilemmal cysts are common hair follicle-derived intradermal cysts. The trait shows an autosomal dominant mode of transmission with incomplete penetrance. Here, we describe the pathogenetic mechanism for the development of hereditary trichilemmal cysts. By whole-exome sequencing of DNA from the blood samples of 5 affected individuals and subsequent Sanger sequencing of a family cohort including 35 affected individuals, this study identified a combination of the Phospholipase C Delta 1 germline variants c.903A>G, p.(Pro301Pro) and c.1379C>T, p.(Ser460Leu) as a high-risk factor for trichilemmal cyst development. Allele-specific PCRs and cloning experiments showed that these two variants are present on the same allele. The analysis of tissue from several cysts revealed that an additional somatic Phospholipase C Delta 1 mutation on the same allele is required for cyst formation. In two different functional in vitro assays, this study showed that the protein function of the cyst-specific 1-phosphatidylinositol 4, 5-bisphosphate phosphodiesterase delta-1 protein variant is modified. This pathologic mechanism defines a monoallelic model of the two-hit mechanism proposed for tumor development and other hereditary cyst diseases.
Find related publications in this database (using NLM MeSH Indexing): Alleles - administration & dosage; Biopsy, Needle - administration & dosage; Epidermal Cyst - genetics, pathology; Female - administration & dosage; Genetic Predisposition to Disease - administration & dosage; Germ-Line Mutation - administration & dosage; Hair Follicle - pathology; Humans - administration & dosage; Immunohistochemistry - administration & dosage; Male - administration & dosage; Pedigree - administration & dosage; Phospholipase C delta - genetics; Real-Time Polymerase Chain Reaction - methods; Scalp - pathology; Skin Diseases - genetics, pathology; Exome Sequencing - administration & dosage