Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1α in autosomal recessive hypotrichosis

Satoru Shinkuma, Masashi Akiyama, Asuka Inoue, Junken Aoki, Ken Natsuga, Toshifumi Nomura, Ken Arita, Riichiro Abe, Kei Ito, Hideki Nakamura, Hideyuki Ujiie, Akihiko Shibaki, Hiraku Suga, Yuichiro Tsunemi, Wataru Nishie, Hiroshi Shimizu

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51 Citations (Scopus)


Autosomal recessive hypotrichosis (ARH) is characterized by sparse hair on the scalp without other abnormalities. Three genes, DSG4, LIPH, and LPAR6 (P2RY5), have been reported to underlie ARH. We performed a mutation search for the three candidate genes in five independent Japanese ARH families and identified two LIPH mutations: c.736T>A (p.Cys246Ser) in all five families, and c.742C>A (p.His248Asn) in four of the five families. Out of 200 unrelated control alleles, we detected c.736T>A in three alleles and c.742C>A in one allele. Haplotype analysis revealed each of the two mutant alleles is derived from a respective founder. These results suggest the LIPH mutations are prevalent founder mutations for ARH in the Japanese population. LIPH encodes PAPLA1α (LIPH), a membrane-associated phosphatidic acid-preferring phospholipase A1α. Two residues, altered by these mutations, are conserved among PA-PLA1α of diverse species. Cys246 forms intramolecular disulfide bonds on the lid domain, a crucial structure for substrate recognition, and His248 is one amino acid of the catalytic triad. Both p.Cys246Ser- and p.His248Asn-PA-PLA1a mutants showed complete abolition of hydrolytic activity and had no P2Y5 activation ability. These results suggest defective activation of P2Y5 due to reduced 2-acyl lysophosphatidic acid production by the mutant PA-PLA1α is involved in the pathogenesis of ARH.

Original languageEnglish
Pages (from-to)602-610
Number of pages9
JournalHuman Mutation
Issue number5
Publication statusPublished - 2010 May


  • Catalytic triad
  • LAH
  • LAH2
  • Lid domain
  • LIPH
  • Lysophosphatidic acid
  • Phosphatidic acid


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