Autosomal Recessive Woolly Hair Research Articles

Molecular Basis of Hereditary Hair Diseases.

The hair follicle is an appendage of the skin that undergoes hair cycles throughout life. Recently, numerous genes expressed in the hair follicles have been identified, and variants in some of these genes are now known to underlie hereditary hair diseases in humans. Hereditary hair diseases are classified into non-syndromic and syndromic forms. In the Japanese population, the non-syndromic form of autosomal recessive woolly hair, which is caused by founder pathogenic variants in the lipase H (LIPH) gene, is the most prevalent hereditary hair disease. In addition, other types of hereditary hair diseases are known in Japan, such as Marie-Unna hereditary hypotrichosis, hypohidrotic ectodermal dysplasia, and tricho-rhino-phalangeal syndrome. To ensure correct diagnoses and appropriate patient care, dermatologists must understand the characteristics of each hair disorder. Elucidation of the molecular basis of hereditary hair diseases can directly tell us which genes are crucial for morphogenesis and development of hair follicles in humans. Therefore, continuation of "wet laboratory" research for these diseases remains important. To date, several syndromic forms of hereditary hair diseases have been approved as designated intractable diseases in Japan. As part of our efforts in the Project for Research on Intractable Diseases through the Ministry of Health, Labour, and Welfare of Japan, we anticipate that more hereditary hair diseases be recognized as designated intractable diseases in the future, which will be to the benefit of the affected individuals.

A Homozygous Missense Variant in K25 Underlying Overlapping Phenotype with Woolly Hair and Dental Anomalies

Autosomal recessive woolly hair with hypotrichosis (ARWH), a rare genetic disorder of hair, is characterized by congenital tightly curled hair, leading to significant thinning of hair later in life (Fujimoto et al., 2012; Khan et al., 2011; Shimomura et al., 2009a, 2009b). Interestingly, many keratin-encoding gene variants have been linked to a wide range of hair, skin, and nail abnormalities (Chamcheu et al., 2011). In humans, 54 keratin genes are known, which encode proteins that are divided into two groups on the basis of their molecular properties: type I (acidic, n = 28) and type II (basic, n = 26).

Evaluation of hair structural abnormalities in children with different neurological diseases

Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in pediatric neurology practice. Children with pathological hair findings were included in our study. Microscopic evaluation of the hair was performed under light microscopy. The clinical findings, pathological hair shaft findings, laboratory tests, and final diagnosis of the patients were evaluated. In our study, 16 patients with rare pathological hair findings were identified. Of these 16 patients, nine were diagnosed with giant axonal neuropathy, three with Griscelli syndrome, two with Menkes disease, and two with autosomal recessive woolly hair disease. In hair inspection, curly and tangled hair in patients with giant axonal neuropathy; silvery blond hair in patients with Griscelli syndrome; sparse, coarse, and light-colored hair in patients with Menkes disease; and hypotrichosis in patients with autosomal recessive woolly hair were remarkable findings. Dystrophic hair was detected in most of the patients on light microscopy. In addition, signs of trichorrhexis nodosa, tricoptylosis, and pili torti were found. In particular, pigment deposition in the hair shaft of two patients diagnosed with Griscelli syndrome and pili torti findings in two patients with Menkes disease were the most important findings suggestingthe diagnosis. Detection of hair findings in the physical examination and performing light microscopic evaluation facilitates the diagnosis of rare diseases accompanied by hair findings. A hair examination should be performed as a part of physical and neurological examinationson eachpatient regardless of thecomplaint.

A case of autosomal recessive woolly hair caused by a mutation in the LIPH gene

A case of autosomal recessive woolly hair caused by a mutation in the LIPH gene

常染色体隐性遗传性羊毛状发一家系基因突变检测

常染色体隐性遗传性羊毛状发一家系基因突变检测

271 Mutation analysis of autosomal recessive woolly hair/ hypotrichosis in 72 Japanese patients

271 Mutation analysis of autosomal recessive woolly hair/ hypotrichosis in 72 Japanese patients

Novel mutations in the lipase H gene lead to secretion defects of LIPH in Chinese patients with autosomal recessive woolly hair/hypotrichosis (ARWH/HT).

Autosomal recessive woolly hair/hypotrichosis (ARWH/HT: OMIM #278150/604379) is a rare hereditary hair disease characterized by tightly curled hair at birth which can lead to sparse hair later in life. The mutations in both LIPH and LPAR6/P2RY5 are responsible for autosomal recessive woolly hair with or without hypotrichosis (ARWH/HT). To conduct clinical and genetic investigations in four patients from three unrelated Chinese Han families with ARWH/HT, we performed mutation screening of LIPH and LPAR6/P2RY5 gene and identified four mutations in LIPH: c.454G>A, c.614A>G, c.736T>A, c.742C>A. c.736T>A and c.742C>A mutations were reported in previous studies, and c.454G>A, c.614A>G were identified for the first time. We carried out functional studies of the two mutants with c.454G>A (p.Gly152Arg, G152R) or c.614A>G (p.His205Arg, H205R). Interestingly, both of them lead to secretion defects of LIPH, which are involved in the pathogenesis of ARWH/HT.

197 A novel splice site mutation in LIPH identified in a Japanese patient with autosomal recessive woolly hair

197 A novel splice site mutation in LIPH identified in a Japanese patient with autosomal recessive woolly hair

A novel deletion mutation in theLPAR6gene underlies autosomal recessive woolly hair with hypotrichosis

A novel deletion mutation in the<i>LPAR6</i>gene underlies autosomal recessive woolly hair with hypotrichosis

Two cases of autosomal recessive woolly hair with LIPH gene mutations

Woolly hair is a hereditary disorder characterized by fine and tightly curled hair. Autosomal recessive woolly hair (ARWH) was recently determined to result from mutations in either the lipase H (LIPH) or the LPAR6 (P2RY5) gene. An 8-year-old boy (proband) and his 11-year-old brother presented with tightly coiled and sparse scalp hair. The boys did not have cardiomyopathy, palmoplantar keratoderma, or facial dysmorphism. Their parents had normal hair growth and no woolly hair. The sequence analysis of their genomic DNA revealed that the proband and his brother had a homozygous mutation of c.736T > A in the LIPH gene. On the basis of these findings, these patients were diagnosed with ARWH. To the best of our knowledge, only 20 cases of ARWH have been previously reported in Japan. However, several reports showed that one mutation was detected in the 4/200 normal and unrelated alleles in healthy Japanese control individuals, indicating the presence of ARWH in patients with extremely mild symptoms.

A Missense Mutation within the Helix Initiation Motif of the Keratin K71 Gene Underlies Autosomal Dominant Woolly Hair/Hypotrichosis

Woolly hair (WH) is an abnormal variant of tightly curled hair, which is frequently associated with hypotrichosis. Non-syndromic forms of WH can show either autosomal-dominant WH (ADWH) or autosomal-recessive WH (ARWH) inheritance patterns. ARWH has recently been shown to be caused by mutations in either the lysophosphatidic acid receptor 6 (LPAR6) or lipase H (LIPH) gene. More recently, a mutation in the keratin K74 (KRT74) gene has been reported to underlie ADWH. Importantly, all of these genes are abundantly expressed in the inner root sheath (IRS) of human hair follicles. Besides these findings, the molecular mechanisms underlying hereditary WH have not been fully disclosed. In this study, we identified a Japanese family with ADWH and associated hypotrichosis. After exclusion of known causative genes, we discovered the heterozygous mutation c.422T>G (p.Phe141Cys) within the helix initiation motif of the IRS-specific keratin K71 (KRT71) gene in affected family members. We demonstrated that the mutant K71 protein led to disruption of keratin intermediate filament formation in cultured cells. To our knowledge, it is previously unreported that the KRT71 mutation is associated with a hereditary hair disorder in humans. Our findings further underscore the crucial role of the IRS-specific keratins in hair follicle development and hair growth in humans.

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

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. 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. 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. 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. Some patients with homozygous c.736T>A can have a mild hypotrichosis phenotype with long hairs in adulthood.

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

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). To study the underlying genetic causes of autosomal woolly hair in Pakistani population. 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. 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. Our study extends the spectrum of mutations in LPAR6/P2RY5 gene and underscores those mutations in LPAR6/P2RY5 and LIPH result in similar phenotypes.

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.

Identification of 736T&gt;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.

A novel deletion mutation in P2RY5/LPA6 gene cause autosomal recessive woolly hair with hypotrichosis

A novel deletion mutation in <i>P2RY5/LPA</i>_<i>6</i> gene cause autosomal recessive woolly hair with hypotrichosis

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

Founder Mutations in the Lipase H Gene in Families with Autosomal Recessive Woolly Hair/Hypotrichosis

Autosomal-recessive woolly hair (ARWH)/hypotrichosis is a hereditary hair disorder which is characterized by tightly curled hair and is associated with sparse hair. ARWH can be caused by mutations in the P2RY5 or lipase H (LIPH) gene. Disruption of either gene results in phenotypes with features of both wooly hair (WH) and hypotrichosis. In this study, we identified two Guyanese families with ARWH. Both families are of recent Indian descent. Mutation analysis resulted in the identification of mutations in the LIPH gene in both families. Affected individuals in the first family carry compound heterozygous mutations Ex7_8del and 1303_1309dupGAAAACG in the LIPH gene, while those in the second family have a homozygous mutation 659_660delTA in the LIPH gene. The mutations Ex7_8del and 659_660delTA were identified earlier in several Pakistani families with ARWH. Haplotype analysis using microsatellite markers close to the LIPH gene defined a founder haplotype shared in families from Pakistan and Guyana. Proteomic analysis of hair shaft samples from one of the families revealed no substantial changes among the proteins identified, indicating that the syndrome does not involve global alterations in protein expression. Our results further suggest a crucial role of LIPH gene in hair growth.

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.