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

Liron Malki, Ofer Sarig, Nicole Cesarato, Janan Mohamad, Talia Canter, Sari Assaf, Mor Pavlovsky, Dan Vodo, Yossi Anis, Ofer Bihari, Kiril Malovitski, Andrea Gat, Holger Thiele, Bethany E.Perez White, Liat Samuelov, Arti Nanda, Amy S. Paller, Regina C. Betz, Eli Sprecher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1227-1234
Number of pages8
JournalGenetics in Medicine
Issue number7
StatePublished - Jul 1 2020


  • C3ORF52
  • alopecia
  • hair
  • hypotrichosis
  • lipase H

ASJC Scopus subject areas

  • Genetics(clinical)


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