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Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA‐PLA 1 α in autosomal recessive hypotrichosis
Author(s) -
Shinkuma Satoru,
Akiyama Masashi,
Inoue Asuka,
Aoki Junken,
Natsuga Ken,
Nomura Toshifumi,
Arita Ken,
Abe Riichiro,
Ito Kei,
Nakamura Hideki,
Ujiie Hideyuki,
Shibaki Akihiko,
Suga Hiraku,
Tsunemi Yuichiro,
Nishie Wataru,
Shimizu Hiroshi
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21235
Subject(s) - biology , genetics , mutant , allele , gene , mutation , compound heterozygosity , haplotype
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 PA‐PLA 1 α (LIPH), a membrane‐associated phosphatidic acid‐preferring phospholipase A 1 α. Two residues, altered by these mutations, are conserved among PA‐PLA 1 α of diverse species. Cys 246 forms intramolecular disulfide bonds on the lid domain, a crucial structure for substrate recognition, and His 248 is one amino acid of the catalytic triad. Both p.Cys246Ser‐ and p.His248Asn‐PA‐PLA 1 α 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‐PLA 1 α is involved in the pathogenesis of ARH. Hum Mutat 31:1–9, 2010. © 2010 Wiley‐Liss, Inc.