P2RY5 Gene Research Articles

Genetic dissection of two Pakistani families with consanguineous localized autosomal recessive hypotrichosis (LAH).

Genetic analysis of two consanguineous Pakistani families with localized autosomal recessive hypotrichosis was performed with the goal to establish genotype-phenotype correlation. Genomic DNA extraction had been done from peripheral blood samples. Extracted DNA was then subjected to PCR (polymerase chain reaction) for amplification. Linkage analysis was performed using 8% polyacrylamide gel. Candidate gene was sequenced after gene linkage supported at highly polymorphic microsatellite markers of the diseased region. Both families were initially tested for linkage to known genes, which were involved in human hereditary hypotrichosis, by genotyping Highly polymorphic microsatellite markers. Family B showed partial linkage at P2RY5 gene on chromosome 13q14.11-q21.32; hence, all exonic regions and their introns boundaries were subjected to DNA sequencing for any pathogenic mutation. Both families were tested for linkage by genotyping polymorphic microsatellite markers linked to known alopecia loci. Family A excluded all known diseased regions that is suggestive of some novel chromosomal disorder. However, sequencing of P2RY5 gene in family B showed no pathogenic mutation.

An Unusual Case of Korean Brother and Sister with Woolly Hair

Dear Editor: Congenital woolly hair is a rare disorder in Asians and Caucasians, resulting from structural defects in the hair shafts. It is characterized by tightly-coiled, fine hair involving the entire, or part of, the scalp of an individual of non-African ethnicity1. Most patients exhibit only woolly hair, without any associated disorders. However, Naxos and Carvajal syndromes are conditions that dermatologists should treat with caution because they can be lethal at an early age, due to a predisposition towards cardiac arrythmias2. A four year old Korean girl and her younger brother presented with woolly hair. Upon closer investigation, tightly curled, easily breakable hairs were evident over the whole scalp. The hairs were very fine, thin and lightly colored (Fig. 1). There were no abnormal conditions associated with their skin, nails, eyelashes, eyebrows, or skeletal and teeth development. They exhibited no mental retardation or cardiomyopathy, and their palms and soles exhibited no hyperkeratosis. The hair of the family, except for the siblings and father side, who had had woolly hair since birth, were normal. Under light microscopy, their hairs exhibited a knotted formation, caliber variation and axis rotation. On scanning electron microscopy, mild cuticular damage was evident as hair shaft weathering (Fig. 2), but hair shaft splintering was not evident, though it has been reported in previous cases. Fig. 1 Very fine, thin and lightly colored curled hairs of siblings were noticed over the whole scalp. Younger brother (B) has more lightly brownish colored hair than his sister (A). Fig. 2 (A) Hair shaft weathering by mild cuticular damage on scanning electron microscopy (×1,000). (B) Cuticular damage seen by transverse section (×1,000). Based on family history, clinical findings and microscopic examinations, we diagnosed the siblings with hereditary congenital woolly hair that is inherited in an autosomal recessive fashion. From the first report of woolly hair by Hutchinson in 1974, Cairns et al. have further classified woolly hair into three variants: woolly hair nevus, autosomal dominant hereditary woolly hair and autosomal recessive familial woolly hair3. One of the three variants, woolly hair nevus, is readily distinguished from the others by a partial involvement of the scalp and a well-circumscribed border that separates the nevus from the otherwise unaffected hair3. Hereditary woolly hair presents as various degrees of tight curling in all hairs throughout the scalp. On the other hand, familial woolly hair is characterized by abnormal, tightly-curled, fine, white or blond hair that tends to be short3. Mutations in the P2RY5 gene, which is expressed in the inner root sheath, encodes recently have been shown responsible for autosomal recessive woolly hair (ARWH). A mutation in P2RY5 may lead to defects in transmitting signals from oleoyl-L-α-lysophosphatidic acid. Therefore, it may affect proliferation and differentiation of inner root sheath cells2,4. Furthermore, it has recently been found that both LPAR6 and lipase H (LIPH) mutations cause ARWH/hypotrichosis. The mechanism of this mutation is based on the regulation of hair follicle development via LPA6 activation by a LIPH-catalyzed lipid mediator4,5. It is difficult to distinguish congenital woolly hair and congenital hypotrichosis, and predict woolly hair will later develop hypotrichosis, because there is no clear genotype-phenotype correlation and clinical variation can occur even within members of the same family4. In conclusion, this report details the first report of siblings with woolly hair (brother and sister) in Korea.

A missense mutation in the P2RY5 gene leading to autosomal recessive woolly hair in a Syrian patient

Chien AJ, 2006, J AM ACAD DERMATOL, V54, pS35, DOI 10.1016-j.jaad.2005.01.092; McKoy G, 2000, LANCET, V355, P2119, DOI 10.1016-S0140-6736(00)02379-5; Norgett EE, 2000, HUM MOL GENET, V9, P2761, DOI 10.1093-hmg-9.18.2761; Pasternack SM, 2008, NAT GENET, V40, P329, DOI 10.1038-ng.84; Shimomura Y, 2008, NAT GENET, V40, P335, DOI 10.1038-ng.100; Shimomura Y, 2009, J INVEST DERMATOL, V129, P622, DOI 10.1038-jid.2008.290; Sonoda H, 2002, J BIOL CHEM, V277, P34254, DOI 10.1074-jbc.M201659200; Takahashi T, 2003, J INVEST DERMATOL, V121, P448, DOI 10.1046-j.1523-1747.2003.12426.x; Tariq M, 2009, BRIT J DERMATOL, V160, P1006, DOI 10.1111-j.1365-2133.2009.09046.x; Yanagida K, 2009, J BIOL CHEM, V284, P17731, DOI 10.1074-jbc.M808506200

Novel mutations in the P2RY5 gene in one Turkish and two Indian patients presenting with hypotrichosis and woolly hair

Hypotrichosis simplex comprises a group of non-syndromic human alopecias. Diffuse loss of hair typically starts in early childhood and progresses throughout adolescence. We and others have previously reported mutations in the P2RY5 gene and the LIPH gene as being causal factors of autosomal recessive hypotrichosis simplex with or without woolly hair. In the present study, we analyzed one Turkish family and two non-related girls of Indian ethnicity affected with hypotrichosis and woolly hair for mutations in these genes. We identified as yet unreported mutations in the P2RY5 gene: a 1-base pair deletion (c.472delC) and a 4-base pair duplication (c.64_67dupTGCA), both of which lead to frameshifts resulting in truncated proteins. Our study increases the spectrum of known P2RY5 mutations and highlights the importance of this receptor in human hair growth and texture.

Mutations in theP2RY5gene underlie autosomal recessive hypotrichosis in 13 Pakistani families

Autosomal recessive hypotrichosis is a rare genetic irreversible hair loss characterized by sparse scalp hair, sparse to absent eyebrows and eyelashes, and sparse axillary and body hair. Affected male individuals have normal beard hair. To search for pathogenic mutations in the human P2RY5 gene in Pakistani families with autosomal recessive hereditary hypotrichosis. In the present report, 16 unrelated consanguineous Pakistani families having multiple affected individuals with autosomal recessive hypotrichosis were investigated. Linkage in these families was searched by genotyping microsatellite markers linked to autosomal recessive hypotrichosis loci LAH1, LAH2 and LAH3. Thirteen of the families showed linkage to the LAH3 locus on chromosome 13q14.11-q21.32. These families were then subjected to direct sequencing of the P2RY5 gene, which encodes a G protein-coupled receptor. Sequence analysis of the P2RY5 gene revealed two novel missense mutations (c.742A>T; p.N248Y and c.830C>T; p.L277P) in three families. Five previously described mutations including three missense (c.188A>T; p.D63V, c.436G>A; p.G146R, c.562A>T; p.I188F), one insertion (c.69insCATG; p.24insHfsX52) and one complex deletion (c.172-175delAACT; 177delG; p.N58-L59delinsCfsX88) were detected in the other 10 families. Mutations revealed in the present study extend the body of evidence implicating the P2RY5 gene in the pathogenesis of human hereditary hair loss.

Mutations in the Lipase H Gene Underlie Autosomal Recessive Woolly Hair/Hypotrichosis

Woolly hair (WH) is characterized by the presence of fine and tightly curled hair. WH can appear as a symptom of some systemic diseases, or without associated findings (nonsyndromic WH). Nonsyndromic WH is known to be inherited as either an autosomal-dominant (OMIM 194300) or recessive (ARWH; OMIM 278150) trait. In this study, we identified 11 consanguineous families of Pakistani origin with ARWH, as well as associated features including sparse and hypopigmented hair shafts. We first checked for mutations in the P2RY5 gene, which encodes an orphan G-protein-coupled receptor that we recently identified as a cause of ARWH. However, none of the 11 families had mutations in the P2RY5 gene. To identify the disease locus, we performed linkage studies in one of these families using the Affymetrix 10K array, and identified a region of suggestive linkage on chromosome 3q27. This region contains the lipase H (LIPH) gene which has been recently shown to underlie an autosomal-recessive form of hypotrichosis. Mutation analysis resulted in the identification of a total of 5 pathogenic mutations in the LIPH of all 11 families analyzed. These results show that LIPH is a second causative gene for ARWH/hypotrichosis, giving rise to a phenotype clinically indistinguishable from P2RY5 mutations.

Autosomal recessive woolly hair with hypotrichosis caused by a novel homozygous mutation in the P2RY5 gene

During the last decade, several causative genes for hereditary hair diseases have been identified, which have disclosed the molecular mechanisms involved in hair follicle morphogenesis and cycling. We and others recently reported that mutations in the P2RY5 gene, encoding an orphan G protein-coupled receptor, underlie autosomal recessive woolly hair (WH)/hypotrichosis. Although these findings clearly reveal the involvement of P2RY5 mutations in hereditary hair diseases, the clinical manifestations of P2RY5 mutations have not completely been elucidated because of limited information to date. In this study, we ascertained a consanguineous family of Iranian origin with an affected girl showing sparse and hypopigmented scalp hair. She exhibited the WH phenotype with normal hair density at birth, but progressed with age to develop hypotrichosis. Direct sequencing analysis resulted in the identification of a novel homozygous mutation in the P2RY5 gene of the patient, which results in a non-conservative amino acid change, G146R, at the protein level. Our findings extend the mutation spectrum of P2RY5 mutations, and further support a crucial role of P2Y5 in hair growth in humans.

Congenital woolly hair withoutP2RY5mutation

Congenital woolly hair is a disorder with structural defects of the hair shafts. Curled hairs are noticed at birth or soon after birth and often improve with age. Some cases of woolly hairs are associated with systemic or other skin diseases. Congenital woolly hair without any associated disorder is inherited in an autosomal dominant or autosomal recessive manner. Recently, mutations in P2RY5 gene, encoding a G-protein coupled receptor, have been shown to be responsible for autosomal recessive woolly hair. Here, we report the second Japanese case of congenital woolly hair, showing no P2RY5 gene mutation.

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.

Novel mutations in G protein-coupled receptor gene (P2RY5) in families with autosomal recessive hypotrichosis (LAH3)

Autosomal recessive hypotrichosis (LAH3) is a rare hair disorder characterized by sparse hair on scalp and the rest of the body of affected individuals. Recently mutations in a G protein-coupled receptor gene, P2RY5, located at LAH3 locus, have been reported in several families with autosomal recessive hypotrichosis simplex and woolly hair. For the present study, 22 Pakistani families with autosomal recessive hypotrichosis were enrolled. Genotyping using microsatellite markers linked to three autosomal recessive forms of hypotrichosis (LAH1, LAH2, LAH3) showed the linkage of 2 families to the LAH2 locus and 14 to the LAH3 locus. The remaining 6 families were not linked to any of the three loci. Families linked to LAH3 locus were further subjected to screening of the P2RY5 gene with direct DNA sequencing. Three previously reported variants, c.69insCATG (p.24insHfs52), c.188A > T (p.D63V) and c.565G > A (p.E189K) were observed in eight families. Four novel nonsynonymous sequence variants, c.8G > C (p.S3T), c.36insA (p.D13RfsX16), c.160insA (p.N54TfsX58) and c.436G > A (p.G146R) were found to segregate within six families.

Common Variants in RB1 Gene and Risk of Invasive Ovarian Cancer

Somatic alteration of the RB1 gene is common in several types of cancer, and germ-line variants are implicated in others. We have used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between common variants (SNP) in RB1 and risks of invasive ovarian cancer. We genotyped 11 tagging SNPs in three ovarian case-control studies from the United Kingdom, United States, and Denmark, comprising >1500 cases and 4,800 controls. Two SNPs showed significant association with ovarian cancer risk: carriers of the minor allele of rs2854344 were at reduced risk compared with the common homozygotes [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.61-0.89; P = 0.0009 dominant model]. Similarly, the minor allele of rs4151620 was found to be associated with reduced risk (rare versus common homozygote; OR, 0.19; 95% CI, 0.07-0.53; P = 0.00005 recessive model). After adjusting for multiple testing, the most significant association (rs4151620) was P = 0.001. A global test comparing common haplotype frequencies in cases and controls was of borderline significance (P(8df) = 0.04). There are no common coding SNPs in the RB1 gene. However, intron 17 of RB1 contains the open reading frame for the P2RY5 gene, and rs4151620 is perfectly correlated with rs2227311, which is located in the 5'-untranslated region of P2RY5 and is predicted to affect P2RY5 transcription. rs2854344 has been reported previously to be associated with breast cancer risk. The possible associations of rs2854344 and rs4151620 with ovarian cancer risk warrant confirmation in independent case-control studies before studies on their biological mode of action.