title: Novel synonymous substitution in POMGNT1 promotes exon skipping in a patient with congenital muscular dystrophy.
abstract: Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy type 1C, and congenital muscular dystrophy type 1D are overlapping clinical entities belonging to a subgroup of the congenital muscular dystrophies (CMD), collectively designated dystroglycanopathies, in which the common underlying defect is hypoglycosylation of alfa-dystroglycan. Currently, six different genes are known to be implicated in these diseases: POMT1, POMT2, POMGNT1, FCMD, FKRP, and LARGE. We report the molecular characterization of a patient presenting clinical features of CMD and reduced immunostaining for alfa-dystroglycan in muscle. Three candidate genes (FCMD, POMT1 and POMGNT1) were analyzed, and a total of 18 sequence variants were detected: 15 polymorphisms in POMT1 [including three unreported single nucleotide polymorphisms (SNPs)], two polymorphisms in FCMD, and the exonic silent mutation c.636C > T in POMGNT1. Expression analysis revealed that this apparently silent mutation compromises correct premessenger RNA (mRNA) splicing, promoting skipping of the entire exon 7, with a consequent frameshift. In silico analysis of this mutation did not predict alterations in the canonical splice sequences, but rather the creation of a new exonic splice silencer. The recognition of such disease-causing elements may contribute to the further understanding of RNA processing and assist mutation screening in routine diagnosis, where such changes may be underestimated. To aid clinical diagnosis, we generated publicly available LOVD-powered Locus Specific Databases for these three genes and recorded all known sequence variants ( http://www.dmd.nl ).
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Soares-Silva
authors.affiliation: Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ivo
authors.initials: I
authors.lastname: Fokkema
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Centro de Desenvolvimento da Criança Luís Borges, Hospital Pediátrico de Coimbra, Coimbra, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cabral
authors.affiliation: Serviço de Metabólicas, Hospital Pediátrico de Coimbra, Coimbra, Portugal.
authors.forename: Luísa
authors.initials: L
authors.lastname: Diogo
authors.affiliation: Serviço de Neuropatologia, Hospital Geral de Santo António, Porto, Portugal.
authors.forename: Lucía
authors.initials: L
authors.lastname: Galán
authors.affiliation: Serviço de Neuropatologia, Hospital Geral de Santo António, Porto, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Guimarães
authors.affiliation: Centro de Desenvolvimento da Criança Luís Borges, Hospital Pediátrico de Coimbra, Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fineza
authors.affiliation: Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Porto, Portugal. rosario.santos@igm.min-saude.pt.
authors.forename: Rosário
authors.initials: R
authors.lastname: Santos
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D004247:DNA / Q000235:genetics; D005091:Exons; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics*; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D009690:Nucleic Acid Conformation; D012322:RNA Precursors / Q000737:chemistry / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics
chemical_list: D012322:RNA Precursors; D004247:DNA; D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase