Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive hypotrichosis.

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.