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 alfadystroglycan 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).

Congenital muscular dystrophies with defective glycosylation of dystroglycan

“…However, the same mutation has recently been shown to compromise correct premessenger RNA (mRNA) splicing, promoting skipping of the entire exon 7, with a consequent frameshift (p.D179VfsX23). 37 A nonsense mutation was detected in the patient with the WWS phenotype (patient 34).…”

Clinical, biochemical and molecular characterization of Cystinuria in a cohort of 12 patients

“…However, this type of situation has been receiving progressive attention (9): a mutation in SLC7A9 that is not per se pathogenic but that certainly contributes to the phenotype and that should be taken into account when predicting the severity of the phenotype. In parallel, there has been increasing acknowledgment that many apparently silent mutations have significant deleterious consequences, causing aberrant splicing or disrupting regulatory sequences (25–27). Functional studies in cells homozygous for these mutations and the study of mRNA from kidney cells would shed more light in this discussion.…”

LAMA2 gene analysis in a cohort of 26 congenital muscular dystrophy patients

“…To this end, mutations need to be contextualized. In those inducing premature termination codons, the extent of nonsense‐mediated mRNA decay needs to be assessed by real‐time RT‐PCR (20, 21, 22) because mRNA stability influences the efficacy of transcript rescue. It is thus foreseeable that future demand on diagnosis will include qualitative and quantitative transcript analysis to identify the cases amenable to the different targeted therapies.…”