Search

Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.

Autosomal recessive proximal spinal muscular atrophy (SMA) is a disease of motor neuron death and a common cause of morbidity in childhood. It has been mapped to 5q13 and shown to be associated with deletions in a gene which has been called the survival motor neuron (SMN) gene. SMN exists in two copies in 5q13 and deletions in exon 7 and 8 of the telomeric copy (SMN tel ) occur in over 90% of patients regardless of disease severity. In contrast, deletion of exon 7 and 8 of the centromeric copy of SMN is present in 3–5% of the normal population. In a minority of patients, exon 7 but not exon 8 of SMN tel appears deleted. The purpose of this study was to analyse this latter type of deletion in more detail. In all patients where there was absence of PCR amplification of exon 7 but not exon 8 of SMN tel this was found to be due to replacement with the homologous copy of SMN cen by a possible gene conversion event. This type of mutation occurred in all grades of severity of SMA.

The 8th annual UK spinal muscular atrophy (SMA) Dr. Eduardo Tizzano (Hospital de Santa Creu i Sant research conference, jointly organised and sponsored by the SMA Trust and the Jennifer Trust for SMA, was held onOctober 3–4, 2011 inOxford, UK.Hosted by Prof. Kevin Talbot at the Oxford Belfry Hotel, the meeting was attended by over 40 researchers and clinicians from across Europe and a total of 17 platform presentations were given. The first day of talks provided a new perspective on the basic functions of the survival motor neuron (SMN) protein, challenged the general assumption that SMA is simply a disorder of the lower motor neuron, and provided interesting ideas on the cause of motor neuron specificity seen in the disease; the second day concentrated on practical aspects of clinical trials in SMA and explored some emerging therapies that are at the cusp of translation to human trials. Presentations on the first day were given by Prof. Michael Sendtner (University of Wurzburg, Germany) on a neuronal specific function of SMN, Dr. Thomas Wishart (University of Edinburgh, UK) on SMN protein expression at the synapse, Dr. Zameel Cader (University of Oxford, UK) on a non-cell autonomous mechanism of neuronal toxicity in distal SMA type V, Dr. Judith Sleeman (University of St. Andrews, UK) on small nuclear ribonucleoprotein dynamics and splicing, Prof. Thomas Gillingwater (University of Edinburgh, UK) on the differential susceptibility of tissues to SMN depletion, Dr. Simon Parson (University of Edinburgh, UK) on the microvasculature in a severe mouse model of SMA, Miss. Maria Gabriela Boza-Moran (University of London, UK) on using stem cells to elucidate pathological mechanisms of SMA, Dr. Heidi Fuller (Keele University, UK) on the proteomic effects of salbutamol treatment on SMA fibroblasts, and