Autosomal dominant centronuclear myopathy is a rare congenital myopathy characterized by delayed motor milestones and muscular weakness. In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.

Objective Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype‐phenotype correlations. Methods Patients were classified into 3 groups: early‐severe (18%), moderate‐progressive (53%), and mild (29%). ColVI secretion was analyzed in patient‐derived skin fibroblasts. Chain‐specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR), and mutation identification was performed by sequencing of complementary DNA. Results ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in‐frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC‐causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in‐frame exon skipping and glycine missense mutations were identified in patients of the moderate‐progressive group (loss of ambulation). Interpretation This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time‐consuming, and demonstrates that quantitative RT‐PCR is a helpful tool for the identification of some mutation‐bearing genes. Moreover, the clinical classification proposed allowed genotype‐phenotype relationships to be explored, and may be useful in the design of future clinical trials. ANN NEUROL 2010;68:511–520

This study reports for the first time the critical role of the Na(v)1.5 N-terminal region in channel function and the dominant-negative effect of trafficking-defective channels occurring through α-subunit interaction.

Very recently, mutations in the TRPM4 gene have been identified in four pedigrees as the cause of an autosomal dominant form of cardiac conduction disease. To determine the role of TRPM4 gene variations, the relative frequency of TRPM4 mutations and associated phenotypes was assessed in a cohort of 160 unrelated patients with various types of inherited cardiac arrhythmic syndromes. In eight probands with atrioventricular block or right bundle branch block--five familial cases and three sporadic cases--a total of six novel and two published TRPM4 mutations were identified. In patients with sinus node dysfunction, Brugada syndrome, or long-QT syndrome, no mutations were found. The novel mutations include six amino acid substitutions and appeared randomly distributed through predicted TRPM4 protein. In addition, eight polymorphic sites including two in-frame deletions were found. Mutations separated from polymorphisms by absence in control individuals and familial cosegregation in some families. In summary, TRPM4 gene mutations appear to play a major role in cardiac conduction disease but not for other related syndromes so far. The phenotypes are variable and clearly suggestive of additional factors modulating the disease phenotype in some patients.

We report four heterozygous dynamin 2 (DNM2) mutations in five centronuclear myopathy patients aged 1 to 15 years. They all presented with neonatal hypotonia with weak suckling. Thereafter, their phenotype progressively improved. All patients demonstrated muscle weakness prominent in the lower limbs, and most of them also presented with facial weakness, open mouth, arched palate, ptosis, and ophthalmoparesis. Electrophysiology showed only myopathic changes, and muscle biopsies showed central nuclei and type 1 fiber hypotrophy and predominance. Our results expand the phenotypic spectrum of dynamin 2-related centronuclear myopathy from the classic mild form to the more severe neonatal phenotype.

Pulmonary arterial hypertension (PAH) is a rare and devastating disease, resulting from progressive obliteration of small caliber pulmonary arteries by proliferating vascular cells, and leading to cardiac failure, with an untreated mean survival of less than three years 1,2. PAH can complicate other pathological conditions, or can occur in the context of genetic mutations causing heritable PAH, or can be considered as idiopathic (iPAH), which represents approximately 40% of all PAH 3,4. Low penetrance dominant BMPR2 mutations are found in ~70% of familial PAH (fPAH), and in ~15% of iPAH which are thereafter considered as heritable PAH 5,6. We conducted a Genome-Wide Association Study (GWAS) based on two independent case-control studies for iPAH and fPAH (without BMPR2 mutations) totaling 625 patients and 1,525 healthy individuals, to identify novel genetic factors associated with iPAH and fPAH (i/fPAH) in the absence of BMPR2 mutations. A genome wide significant association was detected at the CBLN2 locus mapping to 18q22.3, the risk allele being associated with an odds ratio for i/fPAH of 1.97 [1.59 – 2.45] (P = 7.47 x 10−10). CBLN2 is expressed in the lung, particularly in pulmonary vascular endothelial cells, and its expression is increased in explanted lungs from PAH patients and in endothelial cells cultured from explanted PAH lungs.

The importance of O-glycosylation of alpha-dystroglycan (alpha-DG) is evident from the identification of POMT1 mutations in Walker-Warburg syndrome (WWS). Approximately one-fifth of the WWS patients show mutations in POMT1, which result in complete loss of protein mannosyltransferase activity. WWS patients are characterized by congenital muscular dystrophy (CMD) with severe brain and eye abnormalities. This suggests a crucial role for alpha-DG during development of these organs and tissues. Here we report new POMT1 mutations and polymorphisms in WWS patients. In addition, we report different compound heterozygous POMT1 mutations in four unrelated families that result in a less severe phenotype than WWS, characterized by CMD with calf hypertrophy, microcephaly, and mental retardation. Compared to WWS patients, these patients have milder structural brain abnormalities, and eye abnormalities were absent, except for myopia in some cases. In these patients we postulate that one or both transcripts for POMT1 confer residual protein O-mannosyltransferase activity. Our data suggest the existence of a disease spectrum of CMD including brain and eye abnormalities resulting from POMT1 mutations.

Background-Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the ␣-subunit of the cardiac sodium channel Na v 1.5. However, Ϸ20% of probands have SCN5A mutations, suggesting the implication of other genes. MOG1 recently was described as a new partner of Na v 1.5, playing a potential role in the regulation of its expression and trafficking. We investigated whether mutations in MOG1 could cause BrS. Methods and Results-MOG1 was screened by direct sequencing in patients with BrS and idiopathic ventricular fibrillation.A missense mutation p.Glu83Asp (E83D) was detected in a symptomatic female patient with a type-1 BrS ECG but not in 281 controls. Wild type (WT)-and mutant E83D-MOG1 were expressed in HEK Na v 1.5 stable cells and studied using patch-clamp assays. Overexpression of WT-MOG1 alone doubled sodium current (I Na ) density compared to control conditions (PϽ0.01). In contrast, overexpression of mutant E83D alone or E83DϩWT failed to increase I Na (PϽ0.05), demonstrating the dominant-negative effect of the mutant. Microscopy revealed that Na v 1.5 channels failed to properly traffic to the cell membrane in the presence of the mutant. Silencing endogenous MOG1 demonstrated a 54% decrease in I Na density. Conclusions-Our results support the hypothesis that dominant-negative mutations in MOG1 can impair the trafficking of Na v 1.5 to the membrane, leading to I Na reduction and clinical manifestation of BrS. Moreover, silencing MOG1 reduced I Na , demonstrating that MOG1 is likely to be important in the surface expression of Na v 1.5 channels. All together, our data support MOG1 as a new susceptibility gene for BrS. (Circ Cardiovasc Genet. 2011;4:261-268.)