Dual masking of specific negative splicing regulatory elements resulted in maximal exon 7 inclusion of SMN2 gene.

Spinal muscular atrophy (SMA) is a fatal autosomal recessive disease caused by survival motor neuron (SMN) protein insufficiency due to SMN1 mutations. Boosting SMN2 expression is a potential therapy for SMA. SMN2 has identical coding sequence as SMN1 except for a silent C-to-T transition at the 6th nucleotide of exon 7, converting a splicing enhancer to a silencer motif.

A prospective study in the rational design of efficient antisense oligonucleotides for exon skipping in the DMD gene.

Antisense oligonucleotide (AON)-mediated exon skipping to restore dystrophin expression in Duchenne muscular dystrophy (DMD) therapy shown promise in a number of human clinical trials. Current AON design methods are semi-empirical, involving either trial-and-error and/or preliminary experimentations. Therefore, a rational approach to design efficient AONs to address the wide spectrum of patients' mutations is desirable.

Identification and characterisation of human dysferlin transcript variants: implications for dysferlin mutational screening and isoforms.

In conducting dysferlin mutational screening using blood mRNA instead of genomic DNA, we identified the occurrence of alternative splicing involving novel dysferlin exons, i.e. exons 5a and 40a, in addition to previously reported alternative splicing of exon 17.

Two eminently treatable genetic metabolic myopathies.

Treatment of the genetic metabolic myopathies remains generally unsatisfactory with the exception of a select few. Multiple Acyl Co-A Dehydrogenase Deficiency (Glutaric Aciduria type II), in particular, has been shown to respond well to riboflavin supplementation. Recently, studies have also confirmed the effectiveness of recombinant enzyme replacement therapy for Acid Maltase Deficiency (Pompe's Disease).

Fugu rubripes and human survival motor neuron genes: structural and functional similarities in comparative genome studies.

The compactness of the Fugu rubripes (Fugu) genome has supported its use in comparative genome analysis. Nevertheless, as Fugu is distinct evolution-wise from humans, it is essential to determine the similarity between a Fugu gene and its human counterpart to confirm its potential for comparative genome analysis. We cloned and analyzed the Fugu survival motor neuron gene (fsmn) for similarities with human SMN gene (huSMN).

Dynamics of co-transcriptional pre-mRNA folding influences the induction of dystrophin exon skipping by antisense oligonucleotides.

Antisense oligonucleotides (AONs) mediated exon skipping offers potential therapy for Duchenne muscular dystrophy. However, the identification of effective AON target sites remains unsatisfactory for lack of a precise method to predict their binding accessibility. This study demonstrates the importance of co-transcriptional pre-mRNA folding in determining the accessibility of AON target sites for AON induction of selective exon skipping in DMD.

Characterization of a novel S13F desmin mutation associated with desmin myopathy and heart block in a Chinese family.

Desmin myopathy was identified in a Chinese man with complete heart block and mild proximal and distal limb weakness. A novel heterozygous missense S13F mutation of the desmin gene was found to be associated with the myopathy. Family members carrying the mutation showed a similar or milder phenotype.

Identification and characterization of a novel human dysferlin transcript: dysferlin_v1.

Mutations in the dysferlin (DYSF) gene are associated with limb girdle muscular dystrophy type 2B and Miyoshi myopathy. In this study, we report the identification and characterization of a novel dysferlin transcript that we named DYSF_v1 (GenBank accession: DQ267935). This transcript differs from the currently known dysferlin transcript (GenBank accession: AF075575) in the sequence of the entire first exon which spans 232 bases.

Gene transfer to dorsal root ganglia by intrathecal injection: effects on regeneration of peripheral nerves.

Gene delivery to sensory neurons of the dorsal root ganglion (DRG) offers the prospect of developing new clinical interventions against peripheral nerve diseases and disorders. Here we show that genes can be transferred to rat DRG through lumbar intrathecal injection of delivery vectors into the cerebrospinal fluid. Genes could be transferred to DRG using polyethylenimine (PEI)/DNA complexes, Lipofectamine 2000/DNA complexes, adeno-associated virus vectors, or baculovirus vectors.

A novel transthyretin mutation V32A in a Chinese man with late-onset amyloid polyneuropathy.

We report a Chinese patient with amyloidotic polyneuropathy associated with a novel transthyretin mutation (V32A). He presented with slowly progressive sensorimotor polyneuropathy accompanied by autonomic dysfunction and cardiomyopathy by echocardiography. This mutation is likely to be associated with late onset and low-penetrance phenotype.

Peripheral nerve regeneration with sustained release of poly(phosphoester) microencapsulated nerve growth factor within nerve guide conduits.

Prolonged delivery of neurotrophic proteins to the target tissue is valuable in the treatment of various disorders of the nervous system. We have tested in this study whether sustained release of nerve growth factor (NGF) within nerve guide conduits (NGCs), a device used to repair injured nerves, would augment peripheral nerve regeneration. NGF-containing polymeric microspheres fabricated from a biodegradable poly(phosphoester) (PPE) polymer were loaded into silicone or PPE conduits to provide for prolonged, site-specific delivery of NGF.

Serial diffusion-weighted magnetic resonance imaging in adult-onset citrullinaemia.

A 25-year-old Chinese man presented with a 2-year history of recurrent coma. His plasma ammonia level was extremely elevated, with raised citrulline level and absence of argininosuccinic acid. Adult-onset citrullinaemia, a condition rarely reported outside the Japanese population, was diagnosed.