Genetics of human isolated hereditary hair loss disorders

Basit, Sulman; Khan, Saadullah; Ahmad, Wasim

doi:10.1111/cge.12531

Cited by 13 publications

(14 citation statements)

References 90 publications

(161 reference statements)

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“…Thus, mutations within the keratin gene cluster are not likely causal mutations for RTS. Furthermore, all genes reviewed by Basit et al [ 30 ] as causal for hypotrichosis in humans, were excluded as candidates for RTS based on positional data from our linkage and association studies: none of our models or designs indicated a significant locus in one of the respective orthologous bovine chromosomal regions.…”

Section: Discussionmentioning

confidence: 99%

Epistatic interactions between at least three loci determine the “rat-tail” phenotype in cattle

et al. 2016

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BackgroundThe “rat-tail” syndrome (RTS) is an inherited hypotrichosis in cattle, which is exclusively expressed in diluted coloured hair. The affected animals also suffer from disturbed thermoregulation, which impairs their health and growth performance. Phenotypic features that are similar to RTS are observed in dogs with black hair follicle dysplasia.ResultsWe used a resource cross population between German Holstein and Charolais cattle breeds to prove that epistatic interactions between at least three independent genetic loci are required for the expression of the RTS phenotype. In this population, the RTS is exclusively expressed in animals with a eumelanic background that is due to the dominant ED allele at the melanocortin 1 receptor gene located on Bos taurus autosome (BTA) 18. In addition, only the individuals that are heterozygous at the dilution locus on BTA5 that corresponds to the premelanosome protein or silver gene variant c.64G>A were classified as displaying a RTS phenotype. Linkage and whole-genome association analyses using different models and different pedigrees allowed us to map a third locus (hereafter referred to as the RTS locus) that is essential for the expression of the RTS phenotype to the chromosomal region between 14 and 22 Mb on BTA5. Our findings clearly demonstrate that the RTS and dilution loci are distinct loci on BTA5.ConclusionsOur study provides evidence that the RTS locus has effects on hair conformation and coat colour dilution and that the effect on coat colour dilution is clearly independent from that of the dilution locus. Finally, our results excluded several other loci that were previously reported to be associated with or to underlie hair conformation or pigmentation traits as the causal mutations of RTS and also several major functional candidate genes that are associated with hypotrichosis in humans. Our finding on the identification of a three-locus interaction that underlies RTS provides a prime example of epistatic interaction between several independent loci that is required for the expression of a distinct phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12711-016-0199-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Epistatic interactions between at least three loci determine the “rat-tail” phenotype in cattle

et al. 2016

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“…6 Patients with DSG4 mutations show short, twisted, coarse brittle hair shafts called pili torti, which resemble steel wool. 13,14 Unlike in ARWH, the hair shafts in pili torti are bent only slightly at irregular intervals. 13 Trichorrhexis nodosa is a common hair shaft abnormality that can be diagnosed from the characteristic hair shaft appearance suggestive of two brush ends pushed towards each other due to the breakdown of the hair shafts.…”

Section: Differential Diagnoses Of Isolated Arwhmentioning

confidence: 99%

Isolated autosomal recessive woolly hair/hypotrichosis: genetics, pathogenesis and therapies

Akiyama

2021

Acad Dermatol Venereol

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Isolated autosomal recessive woolly hair/hypotrichosis (ARWH) is a rare hereditary hair disease characterized by tightly curled sparse hair at birth or in early infancy. Patients with ARWH consist of genetically heterogeneous groups. Woolly hair autosomal recessive 1 (ARWH1) (MIM #278150), woolly hair autosomal recessive 2 (ARWH2) (MIM #604379) and woolly hair autosomal recessive 3 (ARWH3) (MIM #616760) are caused by mutations in LPAR6, LIPH and KRT25, respectively. In addition, nonsense variants in C3ORF52 (*611956) were identified in ARWH patients. The frequencies of the mutations in the causative genes in ARWH patients are thought to differ by ethnicity and country/geographical area.Large numbers of ARWH families with LIPH mutations have been described only in populations from Japan, Pakistan and the Volga-Ural region of Russia. In that region of Russia, most ARWH families have an extremely prevalent founder mutation, the deletion of exon 4, in LIPH. In the Pakistani population, 47.2% of ARWH families had the disease due to LIPH mutations and 52.8% of them carried LPAR6 mutations. The prevalent, recurrent LIPH mutation c.659_660delTA (p.Ile220Argfs*29) was found in more than half of Pakistani ARWH families with LIPH mutations. Most Japanese ARWH families (98.7%) harbour LIPH mutations, including the two highly prevalent, recurrent LIPH mutations c.736T>A (p.Cys246Ser) and c.742C>A (p.His248Asn). In ARWH patients whose disease was due to LIPH, LPAR6 or C3ORF52 mutations, the loss of function of LIPH, LPAR6 or C3ORF52 leads to reduced LIPH-LPA-LPAR6 signalling, resulting in the decreased transactivation of EGFR signalling and the phenotype of underdeveloped hairs. Our recent prospective interventional study suggests that topical minoxidil might be a promising treatment for ARWH due to LIPH mutations, although sufficiently effective treatments have not been established for ARWH yet.

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“…In syndromic forms, the associated features include ocular anomalies, cardiomyopathy, palmoplantar keratoderma, and skin fragility . The nonsyndromic forms are grouped into three subtypes: a localized form (woolly hair nevus) and two generalized forms including autosomal dominant hereditary woolly hair and autosomal recessive woolly hair . Autosomal dominant WH/H are so far associated with mutations in keratin 71 ( KRT71 ; MIM 608245) and keratin 74 ( KRT74 ; MIM 608248) .…”

Section: Introductionmentioning

confidence: 99%

Biallelic mutations in the LPAR6 gene causing autosomal recessive wooly hair/hypotrichosis phenotype in five Pakistani families

et al. 2019

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Background Autosomal recessive wooly hair/hypotrichosis is an inherited disorder of hair characterized by less dense, short, and tightly curled hair on the scalp and sometimes less dense to complete absence of eyebrows and eyelashes. Autosomal recessive wooly hair/ hypotrichosis phenotypes are mostly associated with pathogenic sequence variants in LIPH and LPAR6 genes.Methods To find out the molecular basis of the disease, five families with autosomal recessive wooly hair/hypotrichosis were recruited for genetic analysis. Direct Sanger sequencing of LIPH and LPAR6 genes was carried out using BigDye chain termination chemistry. P2RY5 protein homology models were developed to study the effect of mutation on protein structure in a family having novel mutation.Results Sanger sequencing revealed a novel homozygous missense mutation (c.47A>T) in the LPAR6 gene in family A, while recurrent mutation (c.436G>A) was detected in the rest of the four families (B-E). Protein homology models for both native and mutant P2RY5 protein were developed to study the difference in subtle structural features because of Lys16Met (K16M) mutation. We observed that P2RY5 K16M mutation results decrease in the number of ionic interactions detrimental to the protein stability. Protein modeling studies revealed that the novel mutation identified here decreased the number of ionic interactions by affecting physicochemical parameters of the protein, leading to an overall decrease in protein stability with no major secondary structural changes.Conclusion The molecular analysis further confirms the frequent involvement of LPAR6 in autosomal recessive wooly hair/hypotrichosis, while the bioinformatic study revealed that the missense mutation destabilizes the overall structure of P2RY5 protein.

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Genetics of human isolated hereditary hair loss disorders

Cited by 13 publications

References 90 publications

Epistatic interactions between at least three loci determine the “rat-tail” phenotype in cattle

Epistatic interactions between at least three loci determine the “rat-tail” phenotype in cattle

Isolated autosomal recessive woolly hair/hypotrichosis: genetics, pathogenesis and therapies

Biallelic mutations in the LPAR6 gene causing autosomal recessive wooly hair/hypotrichosis phenotype in five Pakistani families

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