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Clermont-Ferrand, France

Laberge A.-M.,Service de genetique medicale | Laberge A.-M.,University of Montreal | Burke W.,University of Washington
Seminars in Nephrology | Year: 2010

The clinical utility of many emerging genetic technologies has yet to be established. For many new genetic tests, no practice guidelines are available to help clinicians decide when and how to use them in practice. The clinical and public health implications of new genetic technologies are easiest to evaluate when these tests are compared with other genetic tests, including those already well established in clinical practice. Genetic tests can be divided into different categories based on their intent as follows: (1) to establish a diagnosis (genetic diagnostic tests), (2) to classify disease processes to assist management (gene expression profiling), (3) to predict drug response or side effects (pharmacogenomic tests), and (4) to predict susceptibility to disease (genetic susceptibility testing). As new genetic tests emerge, their translation into practice will depend on their performance based on laboratory standards, but also on their ability to enhance prevention or assist clinicians in diagnosing and treating patients. This article reviews the clinical and public health implications of different types of genetic tests, the evaluation of genetic tests from a public health perspective, and the need for partnership to achieve the potential for benefit of new genetic technologies. © 2010 Elsevier Inc.

Lacombe D.,Bordeaux University Hospital Center | Germain D.P.,Service de genetique medicale | Germain D.P.,University of Versailles
Archives de Pediatrie | Year: 2014

Mucopolysaccharidoses (MPS) are inherited metabolic diseases caused by mutations in the genes coding for one of the eleven enzymes involved in lysosomal catabolism of different glycosaminoglycans (or mucopolysaccharides). The different enzyme deficiencies result in a total of seven distinct mucopolysaccharidoses (I to IV, VI, VII and IX). This review considers the genetic and molecular aspects of the seven types of MPS. © 2014 Elsevier Masson SAS.

Simon D.,University of Bordeaux Segalen | Laloo B.,French Institute of Health and Medical Research | Barillot M.,University of Bordeaux Segalen | Barnetche T.,University of Bordeaux Segalen | And 13 more authors.
Human Molecular Genetics | Year: 2010

A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1. We have identified a variant (c.*281A>T) in the 3′ untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease. The variant is located in the seed sequence of hsa-miR-433. Our data showed that, in MG63 osteosarcoma cells, hsa-miR-433 (miR433) down-regulated both the expression of endogenous HDAC6 and that of an enhanced green fluorescent protein-reporter mRNA bearing the wild-type 3′-UTR of HDAC6. This effect was totally abrogated when the reporter mRNA bore the mutated HDAC6 3′-UTR. The HDAC6 protein was found to be over-expressed in thymus from an affected male fetus. Concomitantly, the level of total α-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated α-tubulin was found to be profoundly decreased. Skin biopsies were obtained from a female patient who presented a striking body asymmetry with hypotrophy of the left limbs. The mutated HDAC6 allele was expressed in 31% of left arm-derived fibroblasts, whereas it was not expressed in the right arm. Overexpression of HDAC6 was observed in left arm-derived fibroblasts. Altogether these results strongly suggest that this HDAC6 3′-UTR variant suppressed hsa-miR-433-mediated post-transcriptional regulation causing the overexpression of HDAC6. This variant is likely to constitute the molecular cause of this new form of X-linked chondrodysplasia. This represents to our knowledge the first example of a skeletal disease caused by the loss of a miRNA-mediated post-transcriptional regulation on its target mRNA. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

Gobin Limballe S.,Service de genetique medicale | McAndrew R.P.,Medical College of Wisconsin | Djouadi F.,University of Paris Descartes | Kim J.J.,Medical College of Wisconsin | Bastin J.,University of Paris Descartes
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2010

Very-Long-Chain Acyl-CoA Dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder considered as one of the more common ß-oxidation defects, possibly associated with neonatal cardiomyopathy, infantile hepatic coma, or adult-onset myopathy. Numerous gene missense mutations have been described in these VLCADD phenotypes, but only few of them have been structurally and functionally analyzed, and the molecular basis of disease variability is still poorly understood. To address this question, we first analyzed fourteen disease-causing amino acid changes using the recently described crystal structure of VLCAD. The predicted effects varied from the replacement of amino acid residues lining the substrate binding cavity, involved in holoenzyme-FAD interactions or in enzyme dimerisation, predicted to have severe functional consequences, up to amino acid substitutions outside key enzyme domains or lying on near enzyme surface, with predicted milder consequences. These data were combined with functional analysis of residual fatty acid oxidation (FAO) and VLCAD protein levels in patient cells harboring these mutations, before and after pharmacological stimulation by bezafibrate. Mutations identified as detrimental to the protein structure in the 3-D model were generally associated to profound FAO and VLCAD protein deficiencies in the patient cells, however, some mutations affecting FAD binding or monomer-monomer interactions allowed a partial response to bezafibrate. On the other hand, bezafibrate restored near-normal FAO rates in some mutations predicted to have milder consequences on enzyme structure. Overall, combination of structural, biochemical, and pharmacological analysis allowed assessment of the relative severity of individual mutations, with possible applications for disease management and therapeutic approach. © 2010 Elsevier B.V.

Srour M.,University of Montreal | Chitayat D.,Prenatal Diagnosis and Medical Genetics Program | Caron V.,University of Montreal | Chassaing N.,Toulouse 1 University Capitole | And 15 more authors.
American Journal of Human Genetics | Year: 2013

Anophthalmia and/or microphthalmia, pulmonary hypoplasia, diaphragmatic hernia, and cardiac defects are the main features of PDAC syndrome. Recessive mutations in STRA6, encoding a membrane receptor for the retinol-binding protein, have been identified in some cases with PDAC syndrome, although many cases have remained unexplained. Using whole-exome sequencing, we found that two PDAC-syndrome-affected siblings, but not their unaffected sibling, were compound heterozygous for nonsense (c.355C>T [p.Arg119*]) and frameshift (c.1201-1202insCT [p.Ile403Serfs*15]) mutations in retinoic acid receptor beta (RARB). Transfection studies showed that p.Arg119* and p.Ile403Serfs*15 altered RARB had no transcriptional activity in response to ligands, confirming that the mutations induced a loss of function. We then sequenced RARB in 15 subjects with anophthalmia and/or microphthalmia and at least one other feature of PDAC syndrome. Surprisingly, three unrelated subjects with microphthalmia and diaphragmatic hernia showed de novo missense mutations affecting the same codon; two of the subjects had the c.1159C>T (Arg387Cys) mutation, whereas the other one carried the c.1159C>A (p.Arg387Ser) mutation. We found that compared to the wild-type receptor, p.Arg387Ser and p.Arg387Cys altered RARB induced a 2- to 3-fold increase in transcriptional activity in response to retinoic acid ligands, suggesting a gain-of-function mechanism. Our study thus suggests that both recessive and dominant mutations in RARB cause anophthalmia and/or microphthalmia and diaphragmatic hernia, providing further evidence of the crucial role of the retinoic acid pathway during eye development and organogenesis. © 2013 The American Society of Human Genetics. All rights reserved.

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