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

BACKGROUND: Hair loss is often experienced by children as a devastating life event. Localized autosomal recessive hypotrichosis (LAH) features progressive and diffuse hair loss since early childhood and has been associated with pathogenic variants in DSG4, encoding a desmosomal protein, as well as in LIPH and LPAR6. LIPH encodes lipase H, which catalyzes the formation of 2-acyl lysophosphatidic acid (LPA), and LPAR6 lysophosphatidic acid receptor 6, a receptor for LPA. LPA promotes hair growth and differentiation in a TGF-a-dependent manner.

OBJECTIVE: We aimed to delineate the genetic basis of LAH in patients without mutations in any of these three genes.
METHODS: Mutation analysis was conducted using whole exome and direct sequencing. We then performed RT-qPCR, immunofluorescence staining, immunoblotting, enzymatic, co-immunoprecipitation and ELISA assays to evaluate the consequences of potential etiologic variants.
RESULTS: We identified homozygous variants in C3ORF52 co-segregating with LAH in two families. C3ORF52 was found to be co-expressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to interact directly. The LAH-causing variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H-mediated LPA biosynthesis and TGF-a signaling.
CONCLUSION: LAH can be caused by abnormal function of at least three proteins that are necessary for proper LPA biosynthesis.