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 PA‐PLA1α (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‐PLA1α 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. Hum Mutat 31:1–9, 2010. © 2010 Wiley‐Liss, Inc.

[1]  A. Christiano,et al.  Mutations in the LIPH gene in three Japanese families with autosomal recessive woolly hair/hypotrichosis. , 2009, Journal of dermatological science.

[2]  M. Nöthen,et al.  In vitro analysis of LIPH mutations causing hypotrichosis simplex: evidence confirming the role of lipase H and lysophosphatidic acid in hair growth. , 2009, The Journal of investigative dermatology.

[3]  A. Tosti,et al.  Mutations in lipase H cause autosomal recessive hypotrichosis simplex with woolly hair. , 2009, Journal of the American Academy of Dermatology.

[4]  A. Christiano,et al.  Founder mutations in the lipase h gene in families with autosomal recessive woolly hair/hypotrichosis. , 2009, The Journal of investigative dermatology.

[5]  M. Nöthen,et al.  A large duplication in LIPH underlies autosomal recessive hypotrichosis simplex in four Middle Eastern families , 2009, Archives of Dermatological Research.

[6]  S. Hodge,et al.  The Effect of Inbreeding on the Distribution of Compound Heterozygotes: A Lesson from Lipase H Mutations in Autosomal Recessive Woolly Hair/Hypotrichosis , 2009, Human Heredity.

[7]  W. Ahmad,et al.  Novel missense mutations in lipase H (LIPH) gene causing autosomal recessive hypotrichosis (LAH2). , 2009, Journal of dermatological science.

[8]  L. Shapiro,et al.  Mutations in the lipase H gene underlie autosomal recessive woolly hair/hypotrichosis. , 2009, The Journal of investigative dermatology.

[9]  P. John,et al.  A novel deletion mutation in the phospholipase H (LIPH) gene in a consanguineous Pakistani family with autosomal recessive hypotrichosis (LAH2) , 2009, The British journal of dermatology.

[10]  W. Ahmad,et al.  A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2) , 2008, Clinical genetics.

[11]  M. Nöthen,et al.  G protein–coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth , 2008, Nature Genetics.

[12]  D. Gordon,et al.  Disruption of P2RY5, an orphan G protein–coupled receptor, underlies autosomal recessive woolly hair , 2008, Nature Genetics.

[13]  P. John,et al.  Localization of a novel autosomal recessive hypotrichosis locus (LAH3) to chromosome 13q14.11–q21.32 , 2007, Clinical genetics.

[14]  P. John,et al.  A mutation in the lipase H (LIPH) gene underlie autosomal recessive hypotrichosis , 2007, Human Genetics.

[15]  H. Arai,et al.  Structure and function of extracellular phospholipase A1 belonging to the pancreatic lipase gene family. , 2007, Biochimie.

[16]  E. Rogaev,et al.  Human Hair Growth Deficiency Is Linked to a Genetic Defect in the Phospholipase Gene LIPH , 2006, Science.

[17]  P. Dempsey,et al.  ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. , 2006, American journal of physiology. Cell physiology.

[18]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[19]  A. Christiano,et al.  A recurrent intragenic deletion in the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis. , 2004, The Journal of investigative dermatology.

[20]  R. Taguchi,et al.  Biochemical and Molecular Characterization of Two Phosphatidic Acid-selective Phospholipase A1s, mPA-PLA1α and mPA-PLA1β* , 2003, Journal of Biological Chemistry.

[21]  P. Gattuso,et al.  Genomic DNA Extraction and PCR Amplification of Exon 15 of the BRAF Gene and Exons 1 and 2 of the NRAS Gene , 2003 .

[22]  S. Leal,et al.  A locus for hereditary hypotrichosis localized to human chromosome 18q21.1 , 2003, European Journal of Human Genetics.

[23]  J. Ott,et al.  Desmoglein 4 in Hair Follicle Differentiation and Epidermal Adhesion Evidence from Inherited Hypotrichosis and Acquired Pemphigus Vulgaris , 2003, Cell.

[24]  N. Whittock,et al.  Genetic evidence for a novel human desmosomal cadherin, desmoglein 4. , 2003, The Journal of investigative dermatology.

[25]  R. Taguchi,et al.  A Novel Phosphatidic Acid-selective Phospholipase A1That Produces Lysophosphatidic Acid* , 2002, The Journal of Biological Chemistry.

[26]  D. Rader,et al.  Lipase H, a new member of the triglyceride lipase family synthesized by the intestine. , 2002, Genomics.

[27]  R. Hondal,et al.  Involvement of the Arg-Asp-His catalytic triad in enzymatic cleavage of the phosphodiester bond. , 2001, Biochemistry.

[28]  H. van Tilbeurgh,et al.  Structural basis for the substrate selectivity of pancreatic lipases and some related proteins. , 1998, Biochimica et biophysica acta.

[29]  H. Ohta,et al.  Detection of K-ras mutations in DNAs isolated from feces of patients with colorectal tumors by mutant-allele-specific amplification (MASA). , 1995, Oncogene.

[30]  R. Taguchi,et al.  Biochemical and molecular characterization of two phosphatidic acid-selective phospholipase A1s, mPA-PLA1alpha and mPA-PLA1beta. , 2003, The Journal of biological chemistry.

[31]  徳丸 晶.  Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing , 2001 .