RSPO4 Is the Major Gene in Autosomal-Recessive Anonychia and Mutations Cluster in the Furin-Like Cysteine-Rich Domains of the Wnt Signaling Ligand R-spondin.

Slides:

Advertisements

Similar presentations

A Novel Missense Mutation in the Second Extracellular Domain of GJB2, p.Ser183Phe, Causes a Syndrome of Focal Palmoplantar Keratoderma with Deafness

Advertisements

Conversion and Compensatory Evolution of the γ-Crystallin Genes and Identification of a Cataractogenic Mutation That Reverses the Sequence of the Human.

Identification of novel missense mutations of the TGFBR3 gene in Chinese women with premature ovarian failure Chun-rong Qin, Shi-ling Chen, Ji-long Yao,

STEVE S. SOMMER, M.D., Ph.D. Mayo Clinic Proceedings

Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal- Recessive Nonsyndromic Hearing Impairment Margit Schraders, Kwanghyuk Lee, Jaap.

Volume 141, Issue 6, Pages (December 2011)

A Novel Mutation and Large Size Polymorphism Affecting the V2 Domain of Keratin 1 in an African-American Family with Severe, Diffuse Palmoplantar Keratoderma.

Next-Generation Sequencing for Mutation Detection in Heritable Skin Diseases: The Paradigm of Pseudoxanthoma Elasticum Andrew P. South, Qiaoli Li, Jouni.

Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A Krista Mahoney, Susan J. Moore, David Buckley, Muhammed Alam, Patrick Parfrey,

P. M. Kelley, D. J. Harris, B. C. Comer, J. W. Askew, T. Fowler, S. D

Gene-Targeted Next Generation Sequencing Identifies PNPLA1 Mutations in Patients with a Phenotypic Spectrum of Autosomal Recessive Congenital Ichthyosis:

Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract Anne E. Hughes, Declan T. Bradley, Malcolm Campbell, Judith Lechner,

Familial Deafness, Congenital Heart Defects, and Posterior Embryotoxon Caused by Cysteine Substitution in the First Epidermal-Growth-Factor–Like Domain.

Dystrophic Epidermolysis Bullosa: COL7A1 Mutation Landscape in a Multi-Ethnic Cohort of 152 Extended Families with High Degree of Customary Consanguineous.

Mutations in the Keratin 85 (KRT85/hHb5) Gene Underlie Pure Hair and Nail Ectodermal Dysplasia Yutaka Shimomura, Muhammad Wajid, Mazen Kurban, Nobuyuki.

High Prevalence of SLC6A8 Deficiency in X-Linked Mental Retardation

Molecular Mechanisms of Junctional Epidermolysis Bullosa: Col15 Domain Mutations Decrease the Thermal Stability of Collagen XVII Laura Väisänen, Cristina.

Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal- Recessive Osteogenesis Imperfecta Jutta Becker, Oliver Semler, Christian.

Aoi Nakano, Hajime Nakano, Sal LaForgia, Leena Pulkkinen, Jouni Uitto

Volume 54, Issue 3, Pages (September 1998)

Tamara Rogers, David Chandler, Dora Angelicheva, P. K

Mutations in a Novel Gene with Transmembrane Domains Underlie Usher Syndrome Type 3 Tarja Joensuu, Riikka Hämäläinen, Bo Yuan, Cheryl Johnson, Saara.

A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele,

Identification of Novel Missense Mutations of Cardiac Ryanodine Receptor Gene in Exercise-Induced Sudden Death at Autopsy Wendy Creighton, Renu Virmani,

Exome Sequencing Identifies SLCO2A1 Mutations as a Cause of Primary Hypertrophic Osteoarthropathy Zhenlin Zhang, Weibo Xia, Jinwei He, Zeng Zhang, Yaohua.

(A) Six missense mutations in six essential genes that are not in annotated functional domains. (A) Six missense mutations in six essential genes that.

Mutations in Contactin-1, a Neural Adhesion and Neuromuscular Junction Protein, Cause a Familial Form of Lethal Congenital Myopathy Alison G. Compton,

A Recurrent Intragenic Deletion in the Desmoglein 4 Gene Underlies Localized Autosomal Recessive Hypotrichosis Celia Moss, Amalia Martinez-Mir, HaMut.

Novel Homozygous and Compound Heterozygous COL17A1 Mutations Associated with Junctional Epidermolysis Bullosa Michaela Floeth, Heike Schäcke, Nadja Hammami-Hauasli,

A Mutation in the Fibroblast Growth Factor 14 Gene Is Associated with Autosomal Dominant Cerebral Ataxia John C. van Swieten, Esther Brusse, Bianca M.

De Novo and Inherited Mutations in COL4A2, Encoding the Type IV Collagen α2 Chain Cause Porencephaly Yuriko Yoneda, Kazuhiro Haginoya, Hiroshi Arai,

Volume 64, Issue 5, Pages (November 2003)

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel.

Mutations of MYO6 Are Associated with Recessive Deafness, DFNB37

Mutations in the Lipase H Gene Underlie Autosomal Recessive Woolly Hair/Hypotrichosis Yutaka Shimomura, Muhammad Wajid, Lynn Petukhova, Lawrence Shapiro,

Recessive Epidermolytic Hyperkeratosis Caused by a Previously Unreported Termination Codon Mutation in the Keratin 10 Gene Patrick Terheyden, Gundula.

Guofang Hu, Meltem Önder, Melissa Gill, Burhan Aksakal, Murat Öztas, M

Airong Li, Sonia Davila, Laszlo Furu, Qi Qian, Xin Tian, Patrick S

Assignment of the Gene for a New Hereditary Nail Disorder, Isolated Congenital Nail Dysplasia, to Chromosome 17p13 Alice Krebsová, Henning Hamm, Susanne.

A Missense Mutation in the Zinc-Finger Domain of the Human Hairless Gene Underlies Congenital Atrichia in a Family of Irish Travellers Wasim Ahmad, Alan.

A Novel Point Mutation Affecting the Tyrosine Kinase Domain of the TRKA Gene in a Family with Congenital Insensitivity to Pain with Anhidrosis Shinichi.

Neil V. Whittock, Gabrielle H. S. Ashton, Patricia J. C

CC2D2A, Encoding A Coiled-Coil and C2 Domain Protein, Causes Autosomal- Recessive Mental Retardation with Retinitis Pigmentosa Abdul Noor, Christian Windpassinger,

Homozygous Dominant Missense Mutation in Keratin 17 Leads to Alopecia in Addition to Severe Pachyonychia Congenita Neil J. Wilson, Mónica L. Cárdenas.

Mutations in R-Spondin 4 (RSPO4) Underlie Inherited Anonychia

R119 is highly conserved, and the p

L. Aravind, Eugene V. Koonin Current Biology

Characterization and Mutation Analysis of Human LEFTY A and LEFTY B, Homologues of Murine Genes Implicated in Left-Right Axis Development K. Kosaki,

Homozygous Variegate Porphyria: Identification of Mutations on Both Alleles of the Protoporphyrinogen Oxidase Gene in a Severely Affected Proband Jorge.

Disruption of ERBB2IP Is not Associated with Dystrophic Epidermolysis Bullosa in Both Father and Son Carrying a Balanced 5;13 Translocation Margarita.

Gabriella Esposito, Giuseppe Rescigno, Francesco Salvatore

Compound Heterozygosity for Novel Splice Site Mutations in the BPAG2/COL17A1 Gene Underlies Generalized Atrophic Benign Epidermolysis Bullosa Leena Pulkkinen,

Molecular Genetics of the Caveolin Gene Family: Implications for Human Cancers, Diabetes, Alzheimer Disease, and Muscular Dystrophy Jeffrey A. Engelman,

Volume 70, Issue 6, Pages (September 2006)

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel.

Clouston Syndrome Can Mimic Pachyonychia Congenita

Homozygous Missense Mutation in Fibulin-5 in an Iranian Autosomal Recessive Cutis Laxa Pedigree and Associated Haplotype Elahe Elahi, Reza Kalhor, Setareh.

A Deletion Mutation in COL17A1 in Five Austrian Families with Generalized Atrophic Benign Epidermolysis Bullosa Represents Propagation of an Ancestral.

Neil V. Whittock, Frances J. Smith, W.H. Irwin McLean

Volume 71, Issue 6, Pages (March 2007)

Missense Mutation in Pseudouridine Synthase 1 (PUS1) Causes Mitochondrial Myopathy and Sideroblastic Anemia (MLASA) Yelena Bykhovskaya, Kari Casas, Emebet.

Identification, by Homozygosity Mapping, of a Novel Locus for Autosomal Recessive Congenital Ichthyosis on Chromosome 17p, and Evidence for Further Genetic.

Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral.

The Tumor-Necrosis-Factor Receptor–Associated Periodic Syndrome: New Mutations in TNFRSF1A, Ancestral Origins, Genotype-Phenotype Studies, and Evidence.

Conversion and Compensatory Evolution of the γ-Crystallin Genes and Identification of a Cataractogenic Mutation That Reverses the Sequence of the Human.

Gene Mutations in the Succinate Dehydrogenase Subunit SDHB Cause Susceptibility to Familial Pheochromocytoma and to Familial Paraganglioma Dewi Astuti,

Volume 97, Issue 6, Pages (June 1999)

Angioid Streaks in Pseudoxanthoma Elasticum: Role of the p

Brachydactyly Type B: Clinical Description, Genetic Mapping to Chromosome 9q, and Evidence for a Shared Ancestral Mutation Yaoqin Gong, David Chitayat,

Homozygous WNT3 Mutation Causes Tetra-Amelia in a Large Consanguineous Family Stephan Niemann, Chengfeng Zhao, Filon Pascu, Ulrich Stahl, Ute Aulepp,

Presentation transcript:

RSPO4 Is the Major Gene in Autosomal-Recessive Anonychia and Mutations Cluster in the Furin-Like Cysteine-Rich Domains of the Wnt Signaling Ligand R-spondin 4 Nadina Ortiz Brüchle, Jorge Frank, Valeska Frank, Jan Senderek, Ahmet Akar, Erol Koc, Dimitris Rigopoulos, Maurice van Steensel, Klaus Zerres, Carsten Bergmann Journal of Investigative Dermatology Volume 128, Issue 4, Pages 791-796 (April 2008) DOI: 10.1038/sj.jid.5701088 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Pedigree and RSPO4 linkage data of the Kazakh family studied. The recombination rates of the informative flanking markers (distally, D20S117 paternally and D20S1156 maternally and D20S199 proximally for both parental haplotypes) in this family are approximately 3cM for the paternal and approximately 5.5cM for the maternal haplotypes. The father of this family was not available for analysis. Therefore, paternal haplotypes in this kindred were deduced from the haplotypes of his children. Bottom left: the right hand of the affected 2-year-old son (left) and the right hand of the affected 15-year-old daughter of this family. The skin in the region of the absent nails was normal, and the nail bed, nail matrix, and fold were present in all fingers and toes (data not shown). Bottom right: electropherogram depicting the novel homozygous nonsense mutation c.301C>T (p.Gln101X) in exon 3 of the RSPO4 gene. Journal of Investigative Dermatology 2008 128, 791-796DOI: (10.1038/sj.jid.5701088) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Pedigree of the Turkish consanguineous family with a total of nine affected individuals. Bottom left: hands and feet of affected individual V-1 showing isolated total congenital anonychia with absence of finger- and toenails. Bottom right: electropherogram depicting the novel, non-conservative homozygous missense mutation c.190C>T that leads to an amino-acid exchange from arginine to cysteine at position 64 (p.Arg64Cys) in exon 2 of the RSPO4 gene. Journal of Investigative Dermatology 2008 128, 791-796DOI: (10.1038/sj.jid.5701088) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Simplified scheme (not drawn to scale) of the RSPO4 gene that spans approximately 44kb of genomic DNA and comprises five exons that encode a secreted protein of 234 amino acids. (Exons are depicted as bars: coding sequence=blackened bar, non-coding exonic sequence=white bar; introns are displayed by lines). RSPO4 mutations detected in this study (underlined) and those described in the literature are shown (blue=splice mutations, red=truncating mutations, green=missense mutations). Bottom left and right: in silico characterization of known RSPO4 missense mutations (the affected arginine residue (p.R64) in the Turkish family is indicated). Multiple protein sequence alignment, generated with ClustalW, of the furin-like cysteine-rich domains encoded by exons 2 and 3. Residues affected by RSPO4 missense mutations are shown on a gray background. Sequence comparison shows that the identified RSPO4 missense mutations affect amino acids that are highly conserved through evolution (bottom left) and among members of the R-spondin protein family (bottom right). Abbreviations and protein annotations used: Hs, Homo sapiens NP_001025042; Mm, Mus musculus BC116367.1; Rn, Rattus norvegicus ENSRNOP00000052312; Cf, Canis familiaris ENSCAFP00000010193; Pt, Pan troglodytes ENSPTRP00000022516; Bt, Bos taurus ENSBTAP00000039099; Ma, Macaca mulatta ENSMMUP00000037654; Md, Monodelphis domestica ENSMODP00000024370; Xt, Xenopus tropicalis ENSXETP00000007765. R-spondin 4 NP_001025042, R 1 NP_001033722, R 2 NP_848660, and R 3 NP_116173. Journal of Investigative Dermatology 2008 128, 791-796DOI: (10.1038/sj.jid.5701088) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions