Different properties of loss-of-function between variants in the LIPH gene responsible for autosomal recessive woolly hair and further characterization of C3orf52.

BACKGROUNDAutosomal recessive woolly hair (ARWH) is a congenital hair disorder characterized by excessively curled scalp hair with limited growth. One of the causative genes, LIPH encoding PA-PLA1α, is involved in a lipid mediator-dependent signaling, and loss-of-function variants in C3orf52 encoding the transmembrane protein associated with PA-PLA1α, have recently been implicated in ARWH. The pathogenic mechanisms for ARWH, however, remain incompletely understood.

OBJECTIVETo characterize LIPH gene-variants responsible for ARWH and to further clarify the molecular properties of C3orf52.

METHODSWild-type and five mutant PA-PLA1α (p.W108R, p.H205R, p.C246S, p.H248N, and p.V437Gfs*4), as well as wild-type C3orf52, were overexpressed in cultured cells, and a series of expression and functional analyzes were performed. C3orf52 expression was additionally assessed in human scalp skin sections.

RESULTSWe demonstrated that the three mutant PA-PLA1α (p.W108R, p.H205R, and p.V437Gfs*4) were not secreted from the cells and induced more severe endoplasmic reticulum stress. We further showed that only the C-terminal variant p.V437Gfs*4 exhibited a significantly reduced binding affinity to C3orf52, consistent with the finding that PA-PLA1α and C3orf52 interacted via their C-termini. In addition, we confirmed that C3orf52 anchored PA-PLA1α on the plasma membrane in cultured cells. Finally, we showed that secretion of the downstream effector TGF-α via the LPA receptor LPA6 was markedly decreased in cells expressing each of the mutant PA-PLA1α proteins tested.

CONCLUSIONOur results indicate that LIPH gene variants cause ARWH through multiple pathogenic pathways, while also providing new insight into the role of C3orf52 in hair follicle development in humans.

Abstract from PubMed