Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome

Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general

Obez / fazla kilolu kadınlarda aktivite isteğinde etkili olan genler ve bunlra bağlı fenotipik ( vki ve bmh) özelliklerin araştırılması

Obezite günümüzde en hızlı yayılan hastalıklar arasında başta gelenlerden biridir. Ülkemizde erkeklerin %20’si ve kadınların % 40’ı olmak üzere, toplumun %30’ undan fazlası obezdir. Birçok kronik hastalığın obeziteyle yakından ilişkili olduğu bilinmektedir . Bu nedenle obezitenin etkenleri ve tedavi seçeneklerini iyi bilmek, obezite ve komplikasyonlarının en uygun tedavisinin belirlenebilmesi açısından önemlidir. Fiziksel aktivite isteği genel olarak çevresel bir faktör olarak bilinse de, ikizlerde yapılan çalışmalar genetik faktörlerin önemli rol oynadığını ortaya koymuştur . yapılan çalışmalarda Lep reseptör geninin egzersiz düzeyini etkileyen faktörler arasında gösterilmiştir. Fiziksel aktivitede azalma, obezitenin en önemli risk faktörlerinden birsi olarak bilinmektedir ancak altta yatan genetik faktörler çok fazla bilinmemektedir. Çalışmamızda Lepr gen mutasyonlarının obezlerde fiziksel aktivite düzeyindeki etkisini göstermeyi amaçladık. Çalışmamızda bu genlerin fiziksel aktivite düzeyleri üzerindeki olası etkilerine ilave olarak vücut kompozisyon parametreleri VKI ( Vücut kütle indeksi), yağsız kütle, yağ kütlesi ( YK), aktivite enerji harcaması ve Dinlenik metabolik hız (DMH) üzerindeki etkileri de araştırılmıştır. Lepr geninin, aktivite düzeyi ile ilişkisini araştırmak için 66 obez/fazla kiolu hasta çalışamaya alınmıştır. Genomik DNA izolasyonu yanak içi epitel dokusundan yapılarak Lepr geni ekzon 6 ve intron 7'nin 446 bç bölgeleri PZR ile çoğaltılmıştır. Aktivite düzeyi Actical cihazının verileri üzerinden hesaplanmıştır. Dizi analizi kullanılarak Lepr genin mutasyonlarının antropometrik, DMH ve aktivite düzeyi parametreler ile ilişkisi araştırılmıştır. Ekzon 6'da Gln223Arg, intron 7' de rs12405556 ve rs11268683 polimorfizmleri saptandı. Egzersiz düzeyi ile polimorfizmler arsında herhangi anlamlılık bulunamamıştır. BMR ve rs12405556 arasında anlamlı ilişki bulunmuştur. Fiziksel aktivite düzeyindeki degişiklikler ile DMH, Yağsız Y arasında anlamlı ilişki bulunamazken, YK, VKI ve aktivite enerji harcaması arasında anlamlı farklılıklar bulunmuştur. Anahtar kelimeler: Aktivite düzeyi , Genetik , Obezite, DMH, VKI SUMMARY Genetic factors of exercise participation and their association with phenotypic traits ( BMR and BMI) in Overweight / Obese Turkish women Obesity is one of the fast spreading diseases. More than 30 % of our population are obese. 20% of men and 40% of women are considered obese. Many chronic diseases are known to be closely related to obesity. Therefore, treatment options and good knowledge of effects of obesity and its complications is important to determine the most appropriate treatment. Physical activity is known as an environmental factor but studies of twins have revealed that genetic factors play an important role. Studies have shown that Lepr gene is among the factors affecting physical activity level. Decreased physical activity is known to be the most important risk factors of obesity, but the underlying genetic factors are not known. In our study, we aimed to show the effect of Lepr gene mutations at the level of physical activity in obese. In our study in addition to the potential impact of Lepr gene on the physical activity levels the impact on body composition parameters Body mass index rate (BMI), Fat free mass (FFM), Fat mass (FM) as well as activity energy consumption and Basal metabolic rate (BMR) were investigated. To investigate the Lepr gene impact on physical activity level, 66 overweight/ obese women patient were included in our study. Genomic DNA was extracted from Buccal cells. Lepr gene regions of exon 6 and 440 bp of intron 7 were amplified by PCR. Physical activity levels calculated by data obtained via Actical accelerometer . Gln 223Arg polymorphism in exon6 and rs12405556 ve rs11268683 were detected in intron 7. No relationship between physical activity levels and Lepr gene was noticed. We found that there was relationship between BMR and rs12405556. We also determined significant relationship between different physical activity levels with FM, BMI and activity energy expenditure while no association was found between FFM and BMR. Key words: Physical activity, Genetic, Obesity, BMR, BM

Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex

Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. LSS encodes lanosterol synthase (LSS), which is a key enzyme in the cholesterol biosynthetic pathway. This pathway plays an important role in hair follicle biology. After localizing LSS protein expression in the hair shaft and bulb of the hair follicle, the impact of the mutations on keratinocytes was analyzed using immunoblotting and immunofluorescence. Interestingly, wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER. A plausible hypothesis is that this mislocalization has potential deleterious implications for hair follicle cells. Immunoblotting revealed no differences in the overall level of wild-type and mutant protein. Analyses of blood cholesterol levels revealed no decrease in cholesterol or cholesterol intermediates, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway. The identification of LSS as causal gene for autosomal-recessive HS highlights the importance of the cholesterol pathway in hair follicle biology and may facilitate novel therapeutic approaches for hair loss disorders in general

Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa

Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI

Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex

Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. LSS encodes lanosterol synthase (LSS), which is a key enzyme in the cholesterol biosynthetic pathway. This pathway plays an important role in hair follicle biology. After localizing LSS protein expression in the hair shaft and bulb of the hair follicle, the impact of the mutations on keratinocytes was analyzed using immunoblotting and immunofluorescence. Interestingly, wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER. A plausible hypothesis is that this mislocalization has potential deleterious implications for hair follicle cells. Immunoblotting revealed no differences in the overall level of wild-type and mutant protein. Analyses of blood cholesterol levels revealed no decrease in cholesterol or cholesterol intermediates, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway. The identification of LSS as causal gene for autosomal-recessive HS highlights the importance of the cholesterol pathway in hair follicle biology and may facilitate novel therapeutic approaches for hair loss disorders in general

Genome-Wide MicroRNA Analysis Implicates miR-30b/d in the Etiology of Alopecia Areata

Alopecia areata (AA) is one of the most common forms of human hair loss. Although genetic studies have implicated autoimmune processes in AA etiology, understanding of the etiopathogenesis is incomplete. Recent research has implicated microRNAs, a class of small noncoding RNAs, in diverse autoimmune diseases. To our knowledge, no study has investigated the role of microRNAs in AA. In this study, gene-based analyses were performed for microRNAs using data of the largest genome-wide association meta-analysis of AA to date. Nominally, significant P -values were obtained for 78 of the 617 investigated microRNAs. After correction for multiple testing, three of the 78 microRNAs remained significant. Of these, miR-30b/d was the most significant microRNA for the follow-up analyses, which also showed lower expression in the hair follicle of AA patients. Target gene analyses for the three microRNAs showed 42 significantly associated target genes. These included IL2RA , TNXB , and ERBB3 , which had been identified as susceptibility loci in previous genome-wide association studies. Using luciferase assay, site-specific miR-30b regulation of the AA risk genes IL2RA, STX17, and TNXB was validated. This study implicates microRNAs in the pathogenesis of AA. This finding may facilitate the development of future treatment strategie

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

In similar to 30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound- heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319 -1G> A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di-and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis

Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

International audienceUncombable hair syndrome (UHS), also known as “spun glass hair syndrome,” “pili trianguli et canaliculi,” or “cheveux incoiffables” is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general