A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K

<p>Abstract</p> <p>Background</p> <p>The ganglioside-induced differentiation-associated protein 1 gene (<it>GDAP1</it>), which is involved in the Charcot-Marie-Tooth disease (CMT), the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying <it>GDAP1 </it>mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB) established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases.</p> <p>Methods and Results</p> <p>We report the development of a publicly accessible LSDB for the <it>GDAP1 </it>gene. The <it>GDAP1</it> LSDB has adopted the Leiden Open-source Variation Database (LOVD) software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the <it>GDAP1 </it>database is illustrated by the finding that <it>GDAP1 </it>mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease.</p> <p>Conclusion</p> <p>Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the <it>GDAP1 </it>LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.</p

Structure et dynamique de neuropeptides liés à leur récepteur

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Various Approaches for Predicting Land Cover in Mountain Areas

Using former maps, geographers intend to study the evolution of the land cover in order to have a prospective approach on the future landscape; predictions of the future land cover, by the use of older maps and environmental variables, are usually done through the GIS (Geographic Information System). We propose here to confront this classical geographical approach with statistical approaches: a linear parametric model (polychotomous regression modeling) and a nonparametric one (multilayer perceptron). These methodologies have been tested on two real areas on which the land cover is known at various dates; this allows us to emphasize the benefit of these two statistical approaches compared to GIS and to discuss the way GIS could be improved by the use of statistical models.Comment: 14 pages; Classifications: Information Theory; Probability Theory & Applications; Statistical Computing; Statistical Theory & Method

Acute and late-onset optic atrophy due to a novel OPA1 mutation leading to a mitochondrial coupling defect

PurposeAutosomal dominant optic atrophy (ADOA, OMIM 165500), an inherited optic neuropathy that leads to retinal ganglion cell degeneration and reduced visual acuity during the early decades of life, is mainly associated with mutations in the OPA1 gene. Here we report a novel ADOA phenotype associated with a new pathogenic OPA1 gene mutation. Methods The patient, a 62-year-old woman, was referred for acute, painless, and severe visual loss in her right eye. Acute visual loss in her left eye occurred a year after initial presentation. MRI confirmed the diagnosis of isolated atrophic bilateral optic neuropathy. We performed DNA sequencing of the entire coding sequence and the exon/intron junctions of the OPA1 gene, and we searched for the mitochondrial DNA mutations responsible for Leber hereditary optic atrophy by sequencing entirely mitochondrial DNA. Mitochondrial respiratory chain complex activity and mitochondrial morphology were investigated in skin fibroblasts from the patient and controls. Results We identified a novel heterozygous missense mutation (c.2794C&gt;T) in exon 27 of the OPA1 gene, resulting in an amino acid change (p.R932C) in the protein. This mutation, which affects a highly conserved amino acids, has not been previously reported, and was absent in 400 control chromosomes. Mitochondrial DNA sequence analysis did not reveal any mutation associated with Leber hereditary optic neuropathy or any pathogenic mutations. The investigation of skin fibroblasts from the patient revealed a coupling defect of oxidative phosphorylation and a larger proportion of short mitochondria than in controls. Conclusions The presence of an OPA1 mutation indicates that this sporadic, late-onset acute case of optic neuropathy is related to ADOA and to a mitochondrial energetic defect. This suggests that the mutational screening of the OPA1 gene would be justified in atypical cases of optic nerve atrophy with no evident cause