title: Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive hypotrichosis.
abstract: 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)alpha (LIPH), a membrane-associated phosphatidic acid-preferring phospholipase A(1)alpha. Two residues, altered by these mutations, are conserved among PA-PLA(1)alpha 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)alpha 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)alpha is involved in the pathogenesis of ARH.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinkuma
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Ken
authors.initials: K
authors.lastname: Natsuga
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Nomura
authors.forename: Ken
authors.initials: K
authors.lastname: Arita
authors.forename: Riichiro
authors.initials: R
authors.lastname: Abe
authors.forename: Kei
authors.initials: K
authors.lastname: Ito
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ujiie
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shibaki
authors.forename: Hiraku
authors.initials: H
authors.lastname: Suga
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tsunemi
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishie
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000483:Alleles; D002460:Cell Line; D002648:Child; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics* / Q000378:metabolism*; D015810:Linkage Disequilibrium; D008049:Lipase / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D054466:Phospholipases A1 / Q000378:metabolism*; D015995:Prevalence; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid
chemical_list: D008049:Lipase; D054466:Phospholipases A1; D018048:Receptors, Purinergic P2; C504173:LIPC protein, human; C082320:LPAR4 protein, human; D049368:Receptors, Lysophosphatidic Acid; C512665:PLA1A protein, human