title: 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-PLA1α 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Genetic Skin Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hayashi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Dermatology, Juntendo University Urayasu Hospital, Urayasu, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Suga
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; CREST, JST, Kawaguchi, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Laboratory of Genetic Skin Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address: yshimo@med.niigata-u.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimomura
mesh_terms: D000328:Adult; D057809:HEK293 Cells; D006197:Hair / Q000002:abnormalities*; D006201:Hair Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics*
chemical_list: C545560:LPAR6 protein, human; D049368:Receptors, Lysophosphatidic Acid
keywords: Hypotrichosis; LIPH; LPA(6); LPAR6; Woolly hair