Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA₁α 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 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.