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Loss-of-function variants in C3ORF52 result in localized autosomal recessive hypotrichosis. 2020

Liron Malki, and Ofer Sarig, and Nicole Cesarato, and Janan Mohamad, and Talia Canter, and Sari Assaf, and Mor Pavlovsky, and Dan Vodo, and Yossi Anis, and Ofer Bihari, and Kiril Malovitski, and Andrea Gat, and Holger Thiele, and Bethany E Perez White, and Liat Samuelov, and Arti Nanda, and Amy S Paller, and Regina C Betz, and Eli Sprecher
Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

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. 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. 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. LAH can be caused by abnormal function of at least three proteins which are necessary for proper LPA biosynthesis.

UI MeSH Term Description Entries
D007039 Hypotrichosis Presence of less than the normal amount of hair. (Dorland, 27th ed) Hypotrichoses
D008246 Lysophospholipids Derivatives of PHOSPHATIDIC ACIDS that lack one of its fatty acyl chains due to its hydrolytic removal. Lysophosphatidic Acids,Lysophospholipid,Acids, Lysophosphatidic
D010375 Pedigree The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition. Family Tree,Genealogical Tree,Genealogic Tree,Genetic Identity,Identity, Genetic,Family Trees,Genealogic Trees,Genealogical Trees,Genetic Identities,Identities, Genetic,Tree, Family,Tree, Genealogic,Tree, Genealogical,Trees, Family,Trees, Genealogic,Trees, Genealogical
D005808 Genes, Recessive Genes that influence the PHENOTYPE only in the homozygous state. Conditions, Recessive Genetic,Genetic Conditions, Recessive,Recessive Genetic Conditions,Condition, Recessive Genetic,Gene, Recessive,Genetic Condition, Recessive,Recessive Gene,Recessive Genes,Recessive Genetic Condition
D006720 Homozygote An individual in which both alleles at a given locus are identical. Homozygotes
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000505 Alopecia Absence of hair from areas where it is normally present. Alopecia, Androgenetic,Baldness,Male Pattern Baldness,Pseudopelade,Alopecia Cicatrisata,Alopecia, Male Pattern,Androgenetic Alopecia,Androgenic Alopecia,Baldness, Male Pattern,Female Pattern Baldness,Hair Loss,Pattern Baldness,Alopecia Cicatrisatas,Alopecia, Androgenic,Alopecias, Androgenic,Androgenic Alopecias,Baldness, Female Pattern,Baldness, Pattern,Hair Losses,Loss, Hair,Losses, Hair,Male Pattern Alopecia
D049368 Receptors, Lysophosphatidic Acid A subfamily of lysophospholipid receptors with specificity for LYSOPHOSPHATIDIC ACIDS. LPA Receptor,Lysophosphatidic Acid Receptor,Lysophosphatidic Acid Receptors,EDG7 Protein,Edg-4 Receptor,Edg-7 Receptor,Edg2 Protein,Edg4 Protein,LPA Receptors,LPA-1 Receptor,LPA1 Receptor,LPA2 Receptor,LPA3 Receptor,Receptor, Lysophosphatidic Acid,edg-2 Receptor,vzg-1 Receptor,Acid Receptor, Lysophosphatidic,Acid Receptors, Lysophosphatidic,Edg 4 Receptor,Edg 7 Receptor,LPA 1 Receptor,Receptor, Edg-4,Receptor, Edg-7,Receptor, LPA,Receptor, LPA1,Receptor, LPA2,Receptor, LPA3,Receptor, edg-2,Receptor, vzg-1,Receptors, LPA,edg 2 Receptor,vzg 1 Receptor
D051182 Desmogleins A group of desmosomal cadherins with cytoplasmic tails that resemble those of classical CADHERINS. Desmoglein

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