Human Mutation

Cover image for Vol. 34 Issue 5

May 2013

Volume 34, Issue 5

Pages v–v, 669–799

  1. Features

    1. Top of page
    2. Features
    3. Mutation Updates
    4. Research Articles
    5. Methods
    1. You have free access to this content
  2. Mutation Updates

    1. Top of page
    2. Features
    3. Mutation Updates
    4. Research Articles
    5. Methods
    1. Mutations in the Genes Encoding the Transcription Factors Hepatocyte Nuclear Factor 1 Alpha and 4 Alpha in Maturity-Onset Diabetes of the Young and Hyperinsulinemic Hypoglycemia (pages 669–685)

      Kevin Colclough, Christine Bellanne-Chantelot, Cecile Saint-Martin, Sarah E. Flanagan and Sian Ellard

      Article first published online: 2 APR 2013 | DOI: 10.1002/humu.22279

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      Frequency and distribution of human hepatocyte nuclear factor 1-alpha (HNF1A) mutations by mutation type within the promoter, 10 exons, and splice sites of the gene. The functional domains of the HNF1A protein are shown; the numbers in boxes refer to the exons. The symbols denote ● missense, ▲ frameshift, ▪ nonsense, ♦ splicing, and * promoter mutations. The four partial and one whole gene deletion of HNF1A are represented by the shaded bars. Please refer to Supp. Table S1 for approved cDNA and protein level mutation names.

    2. Mutation Spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and Genotype–Phenotype Correlations in Warburg Micro Syndrome and Martsolf Syndrome (pages 686–696)

      Mark T. Handley, Deborah J. Morris-Rosendahl, Stephen Brown, Fiona Macdonald, Carol Hardy, Danai Bem, Sarah M. Carpanini, Guntram Borck, Loreto Martorell, Claudia Izzi, Francesca Faravelli, Patrizia Accorsi, Lorenzo Pinelli, Lina Basel-Vanagaite, Gabriela Peretz, Ghada M.H. Abdel-Salam, Maha S. Zaki, Anna Jansen, David Mowat, Ian Glass, Helen Stewart, Grazia Mancini, Damien Lederer, Tony Roscioli, Fabienne Giuliano, Astrid S. Plomp, Arndt Rolfs, John M. Graham, Eva Seemanova, Pilar Poo, Àngels García-Cazorla, Patrick Edery, Ian J. Jackson, Eamonn R. Maher and Irene A. Aligianis

      Article first published online: 11 APR 2013 | DOI: 10.1002/humu.22296

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      Warburg Micro syndrome (OMIM 60018) and Martsolf syndrome (OMIM 21270) are related autosomal recessive neurodevelopmental disorders. Micro syndrome is more severe and characterized by ocular (microphthalmos, microcornea, congenital cataracts and optic atrophy) and neurodevelopmental pathology (microcephaly, polymicrogyria, hypogenesis of the corpus callosum, severe learning disability and progressive limb spasticity) and hypothalamic hypogonadism. Causative germline mutations have been identified in RAB3GAP1 (41% of families), RAB3GAP2 (7% of families) and RAB18 (5% of families) and result in a strikingly consistent phenotype.

  3. Research Articles

    1. Top of page
    2. Features
    3. Mutation Updates
    4. Research Articles
    5. Methods
    1. Mutated Desmoglein-2 Proteins are Incorporated into Desmosomes and Exhibit Dominant-Negative Effects in Arrhythmogenic Right Ventricular Cardiomyopathy (pages 697–705)

      Torsten B. Rasmussen, Johan Palmfeldt, Peter H. Nissen, Raffaela Magnoni, Søren Dalager, Uffe B. Jensen, Won Y. Kim, Lene Heickendorff, Henning Mølgaard, Henrik K. Jensen, Ulrik T. Baandrup, Peter Bross and Jens Mogensen

      Article first published online: 11 MAR 2013 | DOI: 10.1002/humu.22289

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      Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with mutations in the DSG2 gene encoding desmoglein-2, which makes part of desmosomal junctions providing intercellular adhesion between myocardial and epidermal cells. This study investigated expression of desmoglein-2 in keratinocytes and myocardial tissue from ARVC patients and demonstrated that carries of DSG2 mutations express and incorporate mutated desmoglein-2 proteins in myocardial- and epidermal desmosomes. These findings in a patient-specific cell model suggest a dominant-negative effect of three frequent DSG2 mutations associated with ARVC.

    2. Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants in TPP1, The Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease) (pages 706–713)

      Yu Sun, Rowida Almomani, Guido J. Breedveld, Gijs W.E. Santen, Emmelien Aten, Dirk J. Lefeber, Jorrit I. Hoff, Esther Brusse, Frans W. Verheijen, Rob M. Verdijk, Marjolein Kriek, Ben Oostra, Martijn H. Breuning, Monique Losekoot, Johan T. den Dunnen, Bart P. van de Warrenburg and Anneke J.A. Maat-Kievit

      Article first published online: 11 MAR 2013 | DOI: 10.1002/humu.22292

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      Exome sequencing revealed TPP1 as the causative gene for autosomal recessive spinocerebellar ataxia type 7 (SCAR7). A missense and a splice site variant in TPP1, cosegregating with the disease, were found in two SCAR7 families. TPP1, encoding the tripeptidyl peptidase 1 enzyme, is known as the causative gene for neuronal ceroid lipofuscinosis disease 2 (CLN2). Our findings now expand the phenotypes related to TPP1 variants to SCAR7.

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      Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease (pages 714–724)

      Miriam Schmidts, Valeska Frank, Tobias Eisenberger, Saeed al Turki, Albane A. Bizet, Dinu Antony, Suzanne Rix, Christian Decker, Nadine Bachmann, Martin Bald, Tobias Vinke, Burkhard Toenshoff, Natalia Di Donato, Theresa Neuhann, Jane L. Hartley, Eamonn R. Maher, Radovan Bogdanović, Amira Peco-Antić, Christoph Mache, Matthew E. Hurles, Ivana Joksić, Marija Guć-Šćekić, Jelena Dobricic, Mirjana Brankovic-Magic, UK10K, Hanno J. Bolz, Gregory J. Pazour, Philip L. Beales, Peter J. Scambler, Sophie Saunier, Hannah M. Mitchison and Carsten Bergmann

      Article first published online: 11 APR 2013 | DOI: 10.1002/humu.22294

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      Jeune Asphyxiating Thoracic Dysplasia (JATD) is a rare recessive ciliary chondrodysplasia associated with death in infancy due to respiratory failure, and extraskeletal symptoms also occur in some patients. This large next generation sequencing study in 66 JATD and Mainzer-Saldino syndrome (MSS) families reveals that mutations in the intraflagellar transport protein IFT140 cause MSS and are a frequent cause of JATD with retinal and kidney symptoms but mild thorax phenotype, providing for the first time a clinically significant genotype-phenotype association in JATD.

    4. Novel CYP2B6 Enzyme Variants in a Rwandese Population: Functional Characterization and Assessment of In Silico Prediction Tools (pages 725–734)

      Robert Radloff, Alain Gras, Ulrich M. Zanger, Cécile Masquelier, Karthik Arumugam, Jean-Claude Karasi, Vic Arendt, Carole Seguin-Devaux and Kathrin Klein

      Article first published online: 11 MAR 2013 | DOI: 10.1002/humu.22295

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      This study describes new genetic variants of cytochrome P450 (CYP) 2B6 discovered by a sequencing approach in a prevention of mother-to-child HIV transmission cohort from Rwanda and assessment of their functional impact on bupropion and efavirenz hydroxylation activities. Structural modeling and docking analyses helped to understand functional effects of the mutations. Because low-activity alleles of CYP2B6 are associated with impaired efavirenz metabolism and drug response, these results are of potential utility for personalized treatment strategies in HIV/AIDS therapy.

    5. Identification of Functional cis-regulatory Polymorphisms in the Human Genome (pages 735–742)

      Ivan Molineris, Davide Schiavone, Fabio Rosa, Giuseppe Matullo, Valeria Poli and Paolo Provero

      Article first published online: 5 APR 2013 | DOI: 10.1002/humu.22299

    6. Long-Standing Balancing Selection in the THBS4 Gene: Influence on Sex-Specific Brain Expression and Gray Matter Volumes in Alzheimer Disease (pages 743–753)

      Rachele Cagliani, Franca R. Guerini, Raquel Rubio-Acero, Francesca Baglio, Diego Forni, Cristina Agliardi, Ludovica Griffanti, Matteo Fumagalli, Uberto Pozzoli, Stefania Riva, Elena Calabrese, Martin Sikora, Ferran Casals, Giacomo P. Comi, Nereo Bresolin, Mario Cáceres, Mario Clerici and Manuela Sironi

      Article first published online: 2 APR 2013 | DOI: 10.1002/humu.22301

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      The THBS4 gene encodes a glycoprotein involved in inflammation and synaptogenesis. We show that a region in THBS4 represents a balancing selection target. Two major haplogroups are maintained in human populations and modulate THBS4 expression levels in lymphocytes. Variants in the balancing selection region also interact with sex in influencing THBS4 expression in the brain; in Alzheimer disease patients significant interactions between sex and THBS4 genotype were detected for grey matter volumes.

    7. Allele-Specific Expression at the RET Locus in Blood and Gut Tissue of Individuals Carrying Risk Alleles for Hirschsprung Disease (pages 754–762)

      Ivana Matera, Marco Musso, Paola Griseri, Marta Rusmini, Marco Di Duca, Man-ting So, Domenico Mavilio, Xiaoping Miao, Paul HK Tam, Roberto Ravazzolo, Isabella Ceccherini and Merce Garcia-Barcelo

      Article first published online: 15 MAR 2013 | DOI: 10.1002/humu.22302

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      We studied a well-known HSCR (Hirschsprung disease; colon aganglionosis)-associated RET risk haplotype that correlates with reduced RET expression. We investigated whether RET allele-specific expression (ASE) could contribute to the overall reduction of RET mRNA detected in carriers of the risk haplotype. Comparison of RET expression levels between human gut samples with and without ASE, correlated reduced RET expression with preferential transcription from the risk haplotype. RET ASE occurred in ganglionic gut regardless of the disease status.

      Corrected by:

      Erratum: Allele-Specific Expression at the RET Locus in Blood and Gut Tissue of Individuals Carrying Risk Alleles for Hirschsprung Disease

      Vol. 34, Issue 7, 1047, Article first published online: 8 MAY 2013

  4. Methods

    1. Top of page
    2. Features
    3. Mutation Updates
    4. Research Articles
    5. Methods
    1. An MLPA-Based Strategy for Discrete CNV Genotyping: CNV-miRNAs as an Example (pages 763–773)

      Malgorzata Marcinkowska-Swojak, Barbara Uszczynska, Marek Figlerowicz and Piotr Kozlowski

      Article first published online: 8 MAR 2013 | DOI: 10.1002/humu.22288

      Thumbnail image of graphical abstract

      Strategy for MLPA-based assay design for discrete genotyping of selected CNVs. A: Schematic representation map of a CNV-miRNA region. B: Overlapped electropherograms of three DNA samples. C: Two dimensional signal scatter plot depicting the result of copy number genotyping.

    2. You have free access to this content
      A Classification Model Relative to Splicing for Variants of Unknown Clinical Significance: Application to the CFTR Gene (pages 774–784)

      Caroline Raynal, David Baux, Corinne Theze, Corinne Bareil, Magali Taulan, Anne-Françoise Roux, Mireille Claustres, Sylvie Tuffery-Giraud and Marie des Georges

      Article first published online: 5 APR 2013 | DOI: 10.1002/humu.22291

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      More than 1,900 sequence variations have already been reported worldwide in the CFTR gene, including at least 20% variants of unknown clinical significance (VUCS). We built a decision tree for the classification of these VUCS, specifically focused on their consequences on splicing by performing (1) comprehensive review of literature and databases (2) familial genetics data analysis and (3) thorough in silico studies. Our method can play a full role in interpreting the results of molecular diagnosis in emergency context.

    3. Systematic Detection of Pathogenic Alu Element Insertions in NGS-Based Diagnostic Screens: The BRCA1/BRCA2 Example (pages 785–791)

      Sylvia De Brakeleer, Jacques De Grève, Willy Lissens and Erik Teugels

      Article first published online: 11 MAR 2013 | DOI: 10.1002/humu.22297

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      Although 10% of the Human genome consists of Alu elements, only a very small fraction is able to actively retrotranspose eventually resulting in gene inactivation. Alu insertions are however very rarely reported in databases with pathogenic gene variations, most probably because they are missed with the classical PCR based screening procedures. Hereby we present the proof of principle of a NGS-based mutation screening procedure allowing the detection of inherited Alu insertions within any predefined sequence.

    4. Preimplantation Genetic Diagnosis in Genomic Regions with Duplications and Pseudogenes: Long-Range PCR in the Single-Cell Assay (pages 792–799)

      David A. Zeevi, Paul Renbaum, Raphael Ron-El, Talia Eldar-Geva, Arieh Raziel, Baruch Brooks, Dvorah Strassburger, Ehud J. Margalioth, Ephrat Levy-Lahad and Gheona Altarescu

      Article first published online: 19 MAR 2013 | DOI: 10.1002/humu.22298

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      This article describes an accurate method for the diagnosis of mutations in genes, with pseudogene copies, at the single cell level for preimplantation genetic diagnostic purposes. The method is sensitive enough to detect germline mosaicism in single gametes.

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