Mutations in the lipase‐H gene causing autosomal recessive hypotrichosis and woolly hair

Hypotrichosis is characterised by sparse scalp hair, sparse to absent eyebrows and eyelashes, or absence of hair from other parts of the body. In few cases, the condition is associated with tightly curled woolly scalp hair. The present study searched for disease‐causing sequence variants in the genes in four Pakistani lineal consanguineous families exhibiting features of hypotrichosis or woolly hair. A haplotype analysis established links in all four families to the LIPH gene located on chromosome 3q27.2. Subsequently, sequencing LIPH identified a novel non‐sense mutation (c.328C>T; p.Arg110*) in one and a previously reported 2‐bp deletion mutation (c.659_660delTA, p.Ile220ArgfsX29) in three other families.     

Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan

Background. Autosomal recessive hypotrichosis/woolly hair is a rare genetic hair loss disorder characterized by sparse scalp hair/woolly hair, sparse to absent eyebrows and eyelashes, sparse axillary and body hair in affected individuals. This form of hair loss results from mutations in either LPAR6 or LIPH gene. Aim. To identify mutations in LPAR6 and LIPH genes in 17 consanguineous Pakistani families showing features of hypotrichosis/woolly hair. Methods. Genotyping in 17 families was carried out using polymorphic microsatellite markers linked to genes causing autosomal recessive hypotrichosis/woolly hair phenotype. To screen for mutations in LPAR6 and LIPH genes, all of their exons and splice junction sites were amplified by PCR and sequenced using an automated DNA sequencer. Results. Genotyping with polymorphic microsatellite markers showed linkage in eight families to LPAR6 and in nine families to LIPH gene. Sequence analysis revealed four recurrent mutations (p.Phe24HisfsX28; p.Asp63Val; p.Gly146Arg; p.Ile188Phe) in LPAR6 and two recurrent mutations (p.Trp108Arg; p.Ile220ArgfsX29) in LIPH gene. Comparison of the haplotypes generated by typing LPAR6 and LIPH genes linked microsatellite markers in different families suggested common founder natures of the two mutations (c.66_69insCATG and c.659_660delTA). Conclusions. Mutations identified in the present study extend the body of evidence implicating LPAR6 and LIPH genes in pathogenesis of human hereditary hair loss.     

Prevalent founder mutation c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to variable severity of hypotrichosis in adulthood

Background Mutations in LIPH are a cause of autosomal recessive woolly hair (ARWH). Homozygous c.736T>A (p.Cys246Ser), and compound heterozygous c.736T>A and c.742C>A (p.His248Asn) have been reported in 5 and 7 Japanese children with ARWH respectively. The severity of hypotrichosis is known to be able to change in the clinical course, and the mutation patterns of LIPH do not always correlate with the severity of hypotrichosis in ARWH caused by other mutation sites of LIPH. However, all 12 Japanese children previously reported to have ARWH have shown similar severity of hypotrichosis. Objective In this study, we investigated the clinical features and molecular basis of ARWH in patients including three adults (three adults and two children) from five non‐related Japanese families. Methods Five families of Japanese origin that presented with woolly hair were studied. The phenotype was confirmed by clinical examination. Direct automated DNA sequencing of the LIPH gene was performed to identify the mutations in our probands. Results All patients had had woolly hair since birth. Homozygous c.736T>A mutations were found in four patients, including three adult cases, and compound heterozygous c.736T>A and c.742C>A mutations were found in one child patient. The two adults and two children had only sparse scalp hair, although one adult woman had mild hypotrichosis with long hairs. Conclusion Some patients with homozygous c.736T>A can have a mild hypotrichosis phenotype with long hairs in adulthood.     

Novel mutations in the <Emphasis Type="Italic">P2RY5</Emphasis> 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.     

Novel small-insertion mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis

Autosomal recessive woolly hair/hypotrichosis (ARWH/H) is a rare form of congenital alopecia, which can be caused by mutations in lipase H (LIPH), lysophosphatidic acid receptor 6 (LPAR6/P2RY5) or keratin 25 (KRT25) genes. We present a 32-year-old woman with typical clinical features of ARWH. Hair microscopy was performed to observe differences between the patient’s hair and a normal sample. Next-generation sequencing was used to detect pathogenic mutations. Sanger sequencing was used to further confirm the mutations. Abnormal hair appearance was found by hair microscopy. A novel frame-shift mutation (NM_139248: c.686delinsGTAGAACCCAACCTGGCT: p.Asp229fs37X) and a reported mutation (NM_139248: exon6:c.T736A: p.C246S) in LIPH were identified in the patient. All reported mutations related to ARWH of various races were reviewed. Our study provides further evidence of the similarity of ARWH between the Chinese and Japanese population. A novel small-insertion mutation also expands the LIPH mutation spectrum.     

Update of recent findings in genetic hair disorders

Genetic hair disorders, although unusual, are not very rare, and dermatologists often have opportunities to see patients. Significant advances in molecular genetics have led to identifying many causative genes for genetic hair disorders, including the recently identified causative genes, such as LSS and C3ORF52. Many patients have been detected with autosomal recessive woolly hair/hypotrichosis in the Japanese population caused by founder mutations in the LIPH gene. Additionally, many patients with genetic hair disorders caused by other genes have been reported in East Asia including Japan. Understanding genetic hair disorders is essential for dermatologists, and the findings obtained from analyzing these diseases will contribute to revealing the mechanisms of hair follicle morphogenesis and development in humans.     

Mutations in LPAR6/P2RY5 and LIPH are associated with woolly hair and/or hypotrichosis

Background Woolly hair (WH) belongs to a family of disorders characterized by hair shaft anomalies that clinically presents with tightly curled hair, which can be divided into syndromic and non‐syndromic forms of WH. We have recently identified mutations in both LPAR6/P2RY5 and LIPH that are associated with autosomal recessive woolly hair (ARWH). Objective To study the underlying genetic causes of autosomal woolly hair in Pakistani population. Methods We studied 10 Pakistani families with ARWH for mutations in LPAR6/P2RY5 and LIPH and then performed haplotype analysis to confirm their segregation in the families. Results We identified five mutations in LPAR6/P2RY5, among which three were recurrent and two were novel in eight Pakistani families. We then showed that two of the mutations in LPAR6/P2RY5 are founder mutations in Pakistani families. Moreover, we identified two recurrent mutations in the LIPH gene in two Pakistani families. Conclusion Our study extends the spectrum of mutations in LPAR6/P2RY5 gene and underscores those mutations in LPAR6/P2RY5 and LIPH result in similar phenotypes.     

A novel mutation in LPAR6 causes autosomal recessive hypotrichosis of the scalp

Background. Autosomal recessive hypotrichosis simplex (ARHS) presents with progressive hair loss mainly affecting the scalp area. In a small number of families, the condition has been associated with mutations in three distinct genes: DSG4, LIPH and LPAR6. Aim. To identify the molecular basis of ARHS in a consanguineous family of Turkish extraction. Methods. We used a combination of microsatellite marker screening and direct sequencing. Results. We identified a novel missense mutation (c.C587T) in the human LPAR6 gene, resulting in the amino acid substitution p.P196L. The mutation affects a highly conserved amino acid residue, and is predicted to disrupt signalling through the P2Y5 receptor. Conclusions. This study provides further evidence supporting a role for the lysophosphatidyl signalling pathway in hair growth and differentiation. In addition, this paper reports, for the first time to our knowledge, the use of homozygosity mapping as a premutation screening tool in the diagnosis of a group of inherited hair disorders.     

Identification of 736T>A mutation of lipase H in Japanese siblings with autosomal recessive woolly hair

Woolly hair is characterized by fine and tightly curled hair. It has recently been revealed that both LPAR6 and lipase H (LIPH) mutations cause autosomal recessive woolly hair (ARWH)/hypotrichosis. This notion has provided critical evidence to the concept that LPA6 activation by LIPH-catalyzed lipid mediator lysophosphatidic acid has a key role in regulation of hair follicle development. Very recently, novel mutations in exon 6, homozygous 736T>A and compound heterozygous 736T>A and 742C>A have been identified in Japanese ARWH/hypotrichosis patients. Here, we report on siblings (a 7-year-old Japanese girl and her 5-year-old brother) both showing woolly hair. Determination of their genomic sequence showed presence of a homozygous 736T>A transition in exon 6 of the LIPH gene changing cysteine at position 246 to serine, without any mutation in the LPAR6 gene. Additionally, the same mutation was found in one out of a 100 alleles of Japanese healthy controls and identified homozygously in three out of four other Japanese sporadic cases with woolly hair. Collectively, it has been suggested that 736T>A transition is highly specific and common in ARWH/hypotrichosis of Japanese origin.     

Identification of an Alu-mediated 12.2-kb deletion of the complete LPAR6 (P2RY5) gene in a Turkish family with hypotrichosis and woolly hair

Hypotrichosis is a rare form of progressive hair loss characterized by sparse and occasionally woolly hair that is curly and breaks easily. Disease-causing mutations in LIPH, LPAR6 and KRT74 have recently been identified. We describe a four-generation pedigree from Turkey following an autosomal recessive pattern, in which the four affected members had hypotrichosis and woolly hair. By sequencing LPAR6 and the use of SNP arrays, we revealed a homozygous loss of the entire LPAR6 gene in the affected individuals. We hypothesize that the 12-kb deletion resulted from illegitimate recombination secondary to slip-replication. The orientation of three Alu repeats around LPAR6 may have provoked the formation of a 'triple-barrel' structure during replication, thereby allowing strand slipping. This first report of complete LPAR6 loss expands the spectrum of known LPAR6 mutations and suggests a novel mechanism for this gene and for the formation of DNA rearrangements in general.     

Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families

Background  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.
Objectives  To search for pathogenic mutations in the human P2RY5 gene in Pakistani families with autosomal recessive hereditary hypotrichosis.
Methods  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.
Results  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.
Conclusions  Mutations revealed in the present study extend the body of evidence implicating the P2RY5 gene in the pathogenesis of human hereditary hair loss.     

q遗传性秃发／少毛症分子遗传学研究进展

遗传性秃发／少毛症是一组临床少见的遗传性脱发性疾病。近年确定多种遗传性秃发／少毛症的致病基因及其染色体定位,包括Marie—Unna型遗传性少毛症（U2HR,8p21．3）、常染色体显性遗传性单纯性少毛症（APCDDl,18p11．22;RPL21,13q12）、常染色体隐胜遗传性单纯性少毛症（DSG4,18q12．1;DSC3,18q21．1;LIPH,3q26—27;P2RY5,13q13—14;10q11．23—22．3;7p21．3-22-3）、常染色体隐陛遗传性羊毛状发（LIPH,3q26—27;P2RY5,13q13—14）、常染色体显性遗传性羊毛状发（KRT74,12q12—14）和毛囊性鱼鳞病一秃发一畏光综合征（MBTPS2,Xp22）。这些基因在毛囊发生和毛囊生长周期过程中具有重要的调控作用,各种致病性突变均可导致毛囊发生和生长异常,引起秃发／少毛症。     

常染色体显性遗传性少毛症分子遗传学研究进展

遗传性少毛症是一种表现为毛发永久性部分或完全缺失的单基因遗传性疾病,按遗传异质性分为常染色体显性遗传、常染色体隐性遗传、X连锁显性遗传、X连锁隐性遗传。本文重点介绍常染色体显性遗传性少毛症的各种亚型:遗传性单纯性头皮性少毛症(HSS)、遗传性单纯性少毛症(HHS)、Marie Unna型少毛症(MUHH)、常染色体显性羊毛状发(ADWH)、生长期毛发松动综合征(LAHS)等分子遗传学研究进展。     

A case of woolly hair nevus,multiple linear pigmentation,and epidermal nevi with somatic HRAS p.G12S mutation

Woolly hair nevus is a rare syndrome that presents as woolly hair in restricted areas of the scalp and may be associated with pigmented macules or epidermal nevus on the body. Here, we report a case of woolly hair nevus, linear pigmentation, and multiple epidermal nevi with a somatic HRAS c.34G>A(p.G12S) mutation.     

Alopezien und Hypotrichosen im Kindesalter

The monogenic inherited isolated alopecias comprise a group of clinically and genetically heterogeneous disorders with decreased or absent hair. Clinical classification of the isolated alopecias is based upon the onset of the disorder, the regions affected, and the structure of the hair shaft. Men and women are equally affected, and the mode of inheritance is autosomal dominant or autosomal recessive. Therapy does not exist for these rare forms of alopecia. However, molecular genetic diagnosis is possible for the identification of the genetic causes and for the specification of the recurrence risk. Since the identification of the keratin gene KRT86 as a cause of the so called monilethrix in 1997, mutations in eleven other genes have been identified for various isolated alopecias. These include other keratin genes for monilethrix, the HR gene for atrichia congenita, the genes CDSN, APCDD1 and SNRPE for the autosomal dominant form of hypotrichosis simplex, and the genes DSG4, LIPH and LPAR6 for the autosomal recessive forms of hypotrichosis as well as U2HR for hypotrichosis type Marie Unna. Molecular genetic and pathophysiological studies of these rare disorders of hair development have significantly contributed to our understanding of the basic mechanisms of hair loss as well as the physiological mechanisms of hair growth.     

Woolly hair in tricho-dento-osseous syndrome

Tricho-dento-osseous syndrome (TDOS) is a rare ectodermal dysplasia caused by mutations in the DLX3 gene and it is not usually included as a cause of syndromic woolly hair. We present a new case of TDOS with a novel DLX3 variant and woolly hair.     

A novel splice-acceptor site mutation in CDH3 gene in a consanguineous family exhibiting hypotrichosis with juvenile macular dystrophy

Mutations in CDH3 gene, encoding P-cadherin, are responsible for hypotrichosis with juvenile macular dystrophy (HJMD), which is a rare autosomal recessive disorder. The HJMD is characterized by congenital sparse hair on scalp and progressive severe degenerative changes of the retinal macula which leads to variable degrees of blindness. The present study reports a large consanguineous Pakistani family with six individuals affected with HJMD. Genotyping using polymorphic microsatellite markers showed linkage of the family to CDH3 gene on chromosome 16q22.1. Sequence analysis of the CDH3 gene revealed a novel splice site mutation (c.IVS10–1 G → A) in intron 10, which leads to skipping of exon 11 and probably synthesizing a non-functional premature truncated protein.     

Identification of mutations in U2HR in two Chinese families with Marie Unna hereditary hypotrichosis

Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant genodermatosis characterized by coarse, wiry, twisted hair developing during early childhood, with subsequent progressive hair loss. Recently, mutations in U2HR, an inhibitory upstream open reading frame in the 5′ untranslated region of the human hairless gene (HR), were identified as the underlying cause of MUHH. We investigated two unrelated Chinese multigenerational families with MUHH. By sequencing U2HR in the two families, we identified two previously reported mutations, c.1A >T (p.Met1?) and c.104A>G (p*35Wext1263*). Both these mutations cosegregated with the disease phenotype in the two families.