Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis

We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands sample (area under the curve, AUC = 0.65, CI95% = [0.62–0.68], p = 8.3 × 10−22). The maximum AUC achieved was 0.69 (CI95% = [0.66–0.71], p = 4.3 × 10−34) when cell-type proportion was included in the predictor

INVITED REVIEW - Inherited skeletal muscle disorders

The field of inherited skeletal muscle disease research has advanced rapidly since the identification of mutations in the dystrophin gene as the cause of Duchenne muscular dystrophy in 1987. From that point, an ever-increasing number of the genes associated with inherited muscle diseases have been identified. These discoveries have led to much more accurate diagnosis of the individual diseases and have allowed prenatal diagnosis where this was not previously possible. The major challenges for the future are to understand the pathophysiology of the diseases, now that the genes are being identified, and then to develop successful therapies

Identification of point mutations in the dystrophin gene for accurate diagnosis of Duchenne and Becker Muscular Dystrophy

No abstract availabl

Distal myopathies

Purpose of review: The distal myopathies are a heterogeneous group of disorders that pose a challenge to both the clinician and geneticist. This article summarizes the findings of recent clinical, genetic and molecular studies and the current diagnostic approach to this group of patients. Recent findings: Publications over the past 5 years describe a number of new clinical phenotypes and genetic loci and further emphasize the overlap in clinical phenotype between a number of these disorders and between the distal and limb girdle myopathies and hereditary inclusion body myopathies. Recent studies have led to the identification of the genes and mutations responsible for early onset (Laing) myopathy and tibial (Udd) myopathy, and for distal myopathy with rimmed vacuoles (Nonaka), which has been shown to be allelic with quadriceps sparing hereditary inclusion body myopathy (IBM2), and have elucidated the underlying pathogenetic mechanisms in these conditions. New diagnostic approaches using magnetic resonance imaging, and a blood-based assay for dysferlin deficiency, have also been reported. Summary: These findings have important implications for future genetic linkage and gene expression studies and for the diagnostic approach to patients with a distal myopathy phenotype. They also hold promise for the eventual development of therapies for this group of disorders

Revertant fibres: A genetic therapy for duchenne muscular dystrophy?

No abstract availabl

Revertant Fibres: A possible genetic therapy for duchenne muscular dystrophy

No abstract availabl

Verification of carrier status for Becker muscular dystrophy from analysis of a blighted ovum

The polymerase chain reaction (PCR) was used on material from a blighted ovum to confirm indirectly the carrier status of a woman with a family history of Becker muscular dystrophy. Conventional testing including creatine kinase levels, muscle biopsy, and EMG had been inconclusive, and on the basis of one elevated creatine kinase level, the woman had been designated a possible carrier. Ultrasound examination at 10 weeks of pregnancy indicated a blighted ovum, from which DNA was subsequently extracted and subjected to PCR testing for determination of sex and genotypic status with respect to the known familial deletion of the dystrophin gene. The blighted ovum was found to have a Y chromosome and also to be deleted for at least exon 6 of the dystrophin gene, indirectly indicating that the mother most likely carried the family mutation for Becker muscular dystrophy

Characterisation of the chicken Cu, Zn superoxide dismutase gene

A PCR product was generated from embryonic chicken spinal cord cDNA using primers designed to conserved regions of the human and bovine amino and carboxyl-terminal coding sequences of the Cu, Zn superoxide dismutase (SOD1, EC 1.15.1.1) gene. DNA sequencing confirmed this product to be the chicken homologue of the SOD1 gene. This sequence was compared to SOD1 from bovine, human and Xenopus laevis. Important structural features of SOD1 are shown to be conserved in the chicken gene

Dystrophin gene transcripts skipping the mdx mutation

The mdx mouse, an animal model used to study Duchenne muscular dystrophy, has a nonsense mutation in exon 23 of the dystrophin gene which should result in a truncated protein that cannot be correctly localized at the sarcolemma of the muscle fibers. Immunohistochemical staining with antidystrophin antibodies has shown that while most of the muscle tissue is dystrophin-negative, a small percentage of muscle fibers is clearly dystrophin-positive and has somehow bypassed the primary nonsense mutation. A sensitive nested polymerase chain reaction-based examination of dystrophin gene transcripts around the mdx mutation has revealed several alternatively processed transcripts. Four mRNA species skipped the mutation in exon 23, were in-frame, and could be translated into a shorter but still functional dystrophin protein. Specific tests for these transcripts demonstrated these were also present in normal mouse muscle tissu