http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group.

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

/pdf/initial-sequencing-and-comparative-analysis-of-the-mouse-5a9n62pifj.pdf

Initial sequencing and comparative analysis of the mouse genome.

DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.

Functions of DNA methylation: islands, start sites, gene bodies and beyond

Nucleotide and corresponding amino acid sequence of human adult and fetal cDNA coding for portions of the Duchenne muscular dystrophy (DMD) gene.

Intermediate filaments (IFs), along with microfilaments and microtubules, comprise the three intracellular filaments identified in eukaryotic cells to date. Together, these three distinct filamentous networks act in a dynamic and tightly interconnected fashion to comprise the eukaryotic cytoskeleton. As such, they are involved in a number of essential and diverse cellular processes, including division, molecular transport, and the maintenance of structural integrity in the face of mechanical stress. Underscoring the ubiquitous importance of IF proteins to the normal function of cellular systems, mutations in IF-encoding genes that affect the structure, function, or regulation of these proteins are commonly found in association with a range of heritable genetic diseases. The diversity of IF-related disease is indeed as wide as the distribution of IF proteins themselves, effecting the development of a broad range of disease phenotypes. Here we review, with specific reference to recent developments in the correlation of genotype with phenotype, how the perturbation of IF networks can elicit the development of human neurological disease.

The role of intermediate filament proteins in the development of neurological disease.

Spinal muscular atrophy is an autosomal recessive disease of motor neurone degeneration which shows a variable phenotype. Two candidate genes show deletions in affected subjects but with no distinction between different forms of the disease. We report an unusual family in which mild and severe SMA coexists and patients are deleted for the SMN gene. The father is affected with late onset SMA; therefore this family shows pseudodominant inheritance. When typed using closely linked flanking markers the severely affected son does not share the same haplotype as his sib, who is deleted for SMN but shows no signs yet of SMA. This supports the hypothesis that differences in SMA phenotype can be explained by a multiple allele model.

https://jmg.bmj.com/content/jmedgenet/33/12/1019.full.pdf

Evidence for compound heterozygosity causing mild and severe forms of autosomal recessive spinal muscular atrophy.

Duchenne muscular dystrophy (DMD), an allelic X-linked progressive muscle-wasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene- and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene- and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.

/pdf/recent-advances-in-duchenne-muscular-dystrophy-1a14qiopa4.pdf

Recent advances in Duchenne muscular dystrophy.

Losing legislation that has animal welfare at its core would not just jeopardize science, it is also likely to lead to a drop in standards, argues Kay Davies.

Kay E. Davies

Papers

Nucleotide and corresponding amino acid sequence of human adult and fetal cDNA coding for portions of the Duchenne muscular dystrophy (DMD) gene.

The role of intermediate filament proteins in the development of neurological disease.

Evidence for compound heterozygosity causing mild and severe forms of autosomal recessive spinal muscular atrophy.

Recent advances in Duchenne muscular dystrophy.

Keep the directive that protects research animals