Analysis of unique mutations in the LPAR6 gene identified in a Japanese family with autosomal recessive woolly hair/hypotrichosis: Establishment of a useful assay system for LPA6

Abstract Background Woolly hair (WH) is a hair shaft anomaly characterized by tightly-curled hair and is frequently associated with hypotrichosis. Non-syndromic forms of WH can show either autosomal dominant or recessive inheritance. The autosomal recessive form of WH (ARWH) is caused by mutations in either lipase H ( LIPH ) or lysophosphatidic acid receptor 6 ( LPAR6 ) gene, encoding an LPA-producing enzyme PA-PLA1 α and an LPA receptor LPA6 , respectively. Objective To define the molecular basis of ARWH/hypotrichosis in a Japanese family. Methods We performed mutational analysis of candidate genes and a series of expression and in vitro functional analyses, which we improved in this study, to determine the consequences resulting from the mutations identified in the family. Results Novel compound heterozygous LPAR6 mutations were identified in the patient. One was a nonsense mutation c.756T > A (p.Tyr252*); the other was a large insertion mutation within the promoter region of LPAR6 . Expression studies detected LPAR6 mRNA only from the c.756T > A allele in the patient's hair follicles, suggesting that the insertion in the other allele disrupted the LPAR6 promoter and thus led to a failure of transcription. Furthermore, an improved LPA6 functional assay developed in this study demonstrated aberrant expression and a subsequent loss of function of the p.Tyr252*-mutant protein. Conclusion Through establishing a useful assay system for LPA6 , our results further underscore the crucial roles of LPAR6 in hair follicle development and hair growth in humans at molecular levels.