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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.

Pubmed ID: 27866708 RIS Download

Mesh terms: Adolescent | Animals | Antigens | Base Sequence | Cell Line | Codon, Nonsense | Female | Hair | Hair Diseases | Humans | Hydrolases | Intermediate Filament Proteins | Male | Mice | Mice, Knockout | Models, Molecular | Mutation | Mutation, Missense | Protein Conformation | Transglutaminases | Vibrissae

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ImageJ

An open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

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Knockout Mouse Project Repository

Repository of mouse vectors, ES cells, mice, embryos, and sperm generated by the NIH KOMP Mutagenesis Project. In addition, the KOMP Repository offers services in support of the KOMP products, including ES cell microinjection, vector cloning, post-insertional modification of cloned ES cells, cryopreservation, assisted reproduction techniques (IVF, ICSI) and mouse breeding, pathology (clinical and anatomical) pathology services, phenotyping services, etc. The KOMP Repository is the final component of a more than $50 million trans-NIH initiative to increase the availability of genetically altered mice and related materials. The University of California, Davis (UC Davis) and Children''s Hospital Oakland Research Institute (CHORI) in Oakland, Calif., are collaborating to preserve, protect, and make available about 8,500 types of knockout mice and related products available to the research community. The products are generated by two KOMP mutagenesis teams (the CSD consortium and Regeneron Inc). All KOMP products generated by the CSD consortium and Regeneron are available through the KOMP Repository.

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GenBank

NIH genetic sequence database that provides annotated collection of all publicly available DNA sequences for almost 280 000 formally described species (Jan 2014) .These sequences are obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects, including whole-genome shotgun (WGS) and environmental sampling projects. Most submissions are made using web-based BankIt or standalone Sequin programs, and GenBank staff assigns accession numbers upon data receipt. It is part of International Nucleotide Sequence Database Collaboration and daily data exchange with European Nucleotide Archive (ENA) and DNA Data Bank of Japan (DDBJ) ensures worldwide coverage. GenBank is accessible through NCBI Entrez retrieval system, which integrates data from major DNA and protein sequence databases along with taxonomy, genome, mapping, protein structure and domain information, and biomedical journal literature via PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of GenBank database are available by FTP.

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ExAc

An aggregated data platform for genome sequencing data created by a coalition of investigators seeking to aggregate and harmonize exome sequencing data from a variety of large-scale sequencing projects, and to make summary data available for the wider scientific community. The data set provided on this website spans 61,486 unrelated individuals sequenced as part of various disease-specific and population genetic studies. They have removed individuals affected by severe pediatric disease, so this data set should serve as a useful reference set of allele frequencies for severe disease studies. All of the raw data from these projects have been reprocessed through the same pipeline, and jointly variant-called to increase consistency across projects. They ask that you not publish global (genome-wide) analyses of these data until after the ExAC flagship paper has been published, estimated to be in early 2015. If you''re uncertain which category your analyses fall into, please email them. The aggregation and release of summary data from the exomes collected by the Exome Aggregation Consortium has been approved by the Partners IRB (protocol 2013P001477, Genomic approaches to gene discovery in rare neuromuscular diseases).

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NCBI BLAST

Web search tool to find regions of similarity between biological sequences. The program compares nucleotide or protein sequences to sequence databases and calculates the statistical significance.

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OMIM

Online catalog of human genes and genetic disorders, for clinical features, phenotypes and genes. Collection of human genes and genetic phenotypes, focusing on relationship between phenotype and genotype. Referenced overviews in OMIM contain information on all known mendelian disorders and variety of related genes. It is updated daily, and entries contain copious links to other genetics resources.

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Enzyme Nomenclature

Recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology on the nomenclature and classification of enzymes by the reactions they catalyze. Also included are links to individual documents and advice is provided on how to suggest new enzymes for listing, or correction of existing entries. The common names of all listed enzymes are listed, along with their EC numbers. Where an enzyme has been deleted or transferred to another EC number, this information is also indicated. Each list is linked to either separate entries for each entry or to files with up to 50 enzymes in each file. A start has been made in showing the pathways in which enzymes participate. For other enzymes a glossary entry has been added which may be just a systematic name or a link to a graphic representation. The glossary from Enzyme Nomenclature, 1992 may also be consulted. This has been updated with subsequent glossary entries. Each enzyme entry has links to other databases. Enzyme Subclasses provide links to a list of sub-subclasses which in turn list the enzymes linked to separate files for each enzyme, or to a list as part of a file with up to 50 enzymes per file.

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Oxford Gene Technology

Founded by Professor Ed Southern, Oxford Gene Technology (OGT) provides a range of high-quality genomics services, including next generation sequencing (whole exome, pre-designed panels, custom panels, RNA-Seq) and microarray processing (aCGH-CNV, miRNA, gene expression).

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SIFT

Data analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.

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PolyPhen: Polymorphism Phenotyping

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IMPC

Center that produces knockout mice and carries out high-throughput phenotyping of each line in order to determine the function of every gene in the mouse genome. These mice will be preserved in repositories and made available to the scientific community representing a valuable resource for basic scientific research as well as generating new models for human diseases.

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