Genome-wide linkage analysis of an autosomal recessive hypotrichosis identifies a novel P2RY5 mutation.
While there have been significant advances in understanding the genetic etiology of human hair loss over the previous decade, there remain a number of hereditary disorders for which a causative gene has yet to be identified. We studied a large, consanguineous Brazilian family that presented with woolly hair at birth that progressed to severe hypotrichosis by the age of 5, in which 6 of the 14 offspring were affected. After exclusion of known candidate genes, a genome-wide scan was performed to identify the disease locus. Autozygosity mapping revealed a highly significant region of extended homozygosity (lod score of 10.41) that contained a haplotype with a linkage lod score of 3.28. Results of these two methods defined a 9-Mb region on chromosome 13q14.11-q14.2. The interval contains the P2RY5 gene, in which we recently identified pathogenic mutations in several families of Pakistani origin affected with autosomal recessive woolly and sparse hair. After the exclusion of several other candidate genes, we sequenced the P2RY5 gene and identified a homozygous mutation (C278Y) in all affected individuals in this family. Our findings show that mutations in P2RY5 display variable expressivity, underlying both hypotrichosis and woolly hair, and underscore the essential role of P2RY5 in the tissue integrity and maintenance of the hair follicle.
Petukhova
Lynn
L
Department of Dermatology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Sousa
Edilson C
EC
Martinez-Mir
Amalia
A
Vitebsky
Anna
A
Dos Santos
Lina G
LG
Shapiro
Lawrence
L
Haynes
Chad
C
Gordon
Derek
D
Shimomura
Yutaka
Y
Christiano
Angela M
AM
D000595:Amino Acid Sequence; D000818:Animals; D001938:Brazil; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics*; D008126:Lod Score; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D049368:Receptors, Lysophosphatidic Acid
D018048:Receptors, Purinergic P2; C082320:LPAR4 protein, human; D049368:Receptors, Lysophosphatidic Acid