@article {632, title = {Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families.}, journal = {Int J Dermatol}, volume = {56}, year = {2017}, month = {2017 Dec}, pages = {1406-1413}, abstract = {

BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study.

METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families.

RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718~+~2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes.

CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.

}, keywords = {1-Acylglycerol-3-Phosphate O-Acyltransferase, Aldehyde Oxidoreductases, Blister, Collagen Type VII, Consanguinity, DNA Mutational Analysis, DNA-Binding Proteins, Endonucleases, Epidermolysis Bullosa, Epidermolysis Bullosa Dystrophica, Epidermolysis Bullosa Simplex, Exome, Female, Flavoproteins, Homozygote, Humans, Ichthyosiform Erythroderma, Congenital, Ichthyosis Vulgaris, Ichthyosis, Lamellar, INDEL Mutation, Intermediate Filament Proteins, Keratin-14, Lipid Metabolism, Inborn Errors, Lipoxygenase, Male, Membrane Proteins, Mitochondrial Proteins, Muscular Diseases, Neoplasm Proteins, Nuclear Proteins, Pedigree, Periodontal Diseases, Phenotype, Photosensitivity Disorders, Porphyria, Variegate, Protoporphyrinogen Oxidase, Rare Diseases, Sjogren-Larsson Syndrome, Skin Diseases, Genetic, Transcription Factors, Xeroderma Pigmentosum}, issn = {1365-4632}, doi = {10.1111/ijd.13778}, author = {Shah, Khadim and Mehmood, Sabba and Jan, Abid and Abbe, Izoduwa and Hussain Ali, Raja and Khan, Anwar and Chishti, Muhammad S and Lee, Kwanghyuk and Ahmad, Farooq and Ansar, Muhammad and Shahzad, Shaheen and Nickerson, Deborah A and Bamshad, Michael J and Coucke, Paul J and Santos-Cortez, Regie L P and Spritz, Richard A and Leal, Suzanne M and Ahmad, Wasim} } @article {89, title = {Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Feb 04}, pages = {331-8}, abstract = {

The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among \~{}120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2(-/-) mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were~observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2(-/-) mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2.

}, keywords = {Amino Acid Sequence, Asian Continental Ancestry Group, Chromosomes, Human, Pair 19, Exome, Genes, Recessive, Hearing Loss, Humans, Lod Score, Logistic Models, Lysophospholipids, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Receptors, Lysosphingolipid, Sphingosine}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.12.004}, author = {Santos-Cortez, Regie Lyn P and Faridi, Rabia and Rehman, Atteeq U and Lee, Kwanghyuk and Ansar, Muhammad and Wang, Xin and Morell, Robert J and Isaacson, Rivka and Belyantseva, Inna A and Dai, Hang and Acharya, Anushree and Qaiser, Tanveer A and Muhammad, Dost and Ali, Rana Amjad and Shams, Sulaiman and Hassan, Muhammad Jawad and Shahzad, Shaheen and Raza, Syed Irfan and Bashir, Zil-E-Huma and Smith, Joshua D and Nickerson, Deborah A and Bamshad, Michael J and Riazuddin, Sheikh and Ahmad, Wasim and Friedman, Thomas B and Leal, Suzanne M} }