Liron Malki1,2, Ofer Sarig1, Nicole Cesarato3, Janan Mohamad1,2, Talia Canter4, Sari Assaf1,2, Mor Pavlovsky1, Dan Vodo1,2, Yossi Anis5, Ofer Bihari1, Kiril Malovitski1,2, Andrea Gat1, Holger Thiele6, Bethany E Perez White4, Liat Samuelov1, Arti Nanda7, Amy S Paller4, Regina C Betz3, Eli Sprecher8,9. 1. Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 2. Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel. 3. Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany. 4. Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 5. Institute of Endocrinology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 6. Cologne Center for Genomics, University of Cologne, Cologne, Germany. 7. As'ad Al-Hamad Dermatology Center, Kuwait, Kuwait. 8. Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. elisp@tlvmc.gov.il. 9. Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel. elisp@tlvmc.gov.il.
Abstract
PURPOSE: Localized autosomal recessive hypotrichosis (LAH) has been associated with pathogenic variants in DSG4, encoding a desmosomal protein as well as in LIPH and LPAR6, encoding respectively lipase H, which catalyzes the formation of 2-acyl-lysophosphatidic acid (LPA), and lysophosphatidic acid receptor 6, a receptor for LPA. LPA promotes hair growth and differentiation. In this study we aimed at delineating the genetic basis of LAH in patients without pathogenic variants in these three genes. METHODS: Variant analysis was conducted using exome and direct sequencing. We then performed quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunofluorescence staining, immunoblotting, enzymatic, and coimmunoprecipitation assays to evaluate the consequences of potential etiologic variants. RESULTS: We identified homozygous variants in C3ORF52 in four individuals with LAH. C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The LAH-causing variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H-mediated LPA biosynthesis. CONCLUSION: LAH can be caused by abnormal function of at least three proteins which are necessary for proper LPA biosynthesis.
PURPOSE: Localized autosomal recessive hypotrichosis (LAH) has been associated with pathogenic variants in DSG4, encoding a desmosomal protein as well as in LIPH and LPAR6, encoding respectively lipase H, which catalyzes the formation of 2-acyl-lysophosphatidic acid (LPA), and lysophosphatidic acid receptor 6, a receptor for LPA. LPA promotes hair growth and differentiation. In this study we aimed at delineating the genetic basis of LAH in patients without pathogenic variants in these three genes. METHODS: Variant analysis was conducted using exome and direct sequencing. We then performed quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunofluorescence staining, immunoblotting, enzymatic, and coimmunoprecipitation assays to evaluate the consequences of potential etiologic variants. RESULTS: We identified homozygous variants in C3ORF52 in four individuals with LAH. C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The LAH-causing variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H-mediated LPA biosynthesis. CONCLUSION: LAH can be caused by abnormal function of at least three proteins which are necessary for proper LPA biosynthesis.
Entities:
Keywords:
C3ORF52; alopecia; hair; hypotrichosis; lipase H
Authors: F Jung; H Lawall; H Kiesewetter; U Knoop; H J Schönenberger; M Frank; P Hellstern; F C Sitzmann; K F Weinges Journal: Dtsch Med Wochenschr Date: 1987-01-30 Impact factor: 0.628