Novel synonymous substitution in POMGNT1 promotes exon skipping in a patient with congenital muscular dystrophy.
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 ).
Oliveira
Jorge
J
Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Porto, Portugal.
Soares-Silva
Isabel
I
Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Porto, Portugal.
Fokkema
Ivo
I
Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Gonçalves
Ana
A
Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Porto, Portugal.
Cabral
Alexandra
A
Centro de Desenvolvimento da Criança Luís Borges, Hospital Pediátrico de Coimbra, Coimbra, Portugal.
Diogo
Luísa
L
Serviço de Metabólicas, Hospital Pediátrico de Coimbra, Coimbra, Portugal.
Galán
Lucía
L
Serviço de Neuropatologia, Hospital Geral de Santo António, Porto, Portugal.
Guimarães
António
A
Serviço de Neuropatologia, Hospital Geral de Santo António, Porto, Portugal.
Fineza
Isabel
I
Centro de Desenvolvimento da Criança Luís Borges, Hospital Pediátrico de Coimbra, Coimbra, Portugal.
den Dunnen
Johan T
JT
Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Santos
Rosário
R
Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Porto, Portugal. rosario.santos@igm.min-saude.pt.
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
D012322:RNA Precursors; D004247:DNA; D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase