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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Noreau, Anne Darios, Frédéric Loureiro, José L. Coutinho, Paula Depienne, Christel Brice, Alexis Gauthier, Julie Dionne-Laporte, Alexandre Zuchner, Stephan El-Hachimi, Khalid H. Esteves, Typhaine Boutry, Maxime Deleuze, Jean-François Gonzalez, Michael A. Dion, Patrick Muriel, Marie-Paule Durr, Alexandra Stevanin, Giovanni Mundwiller, Emeline Speziani, Fiorella Acosta Lebrigio, Rafael F. Rouleau, Guy A. Gaussen, Marion |
| Description | Author Affiliation: Esteves T ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Durr A ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Mundwiller E ( Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.); Loureiro JL ( UnIGENe and Centro de Genetica Preditiva e Preventiva, Institute for Molecular and Cellular Biology, 4050 Porto, Portugal.); Boutry M ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Gonzalez MA ( Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.); Gauthier J ( Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.); El-Hachimi KH ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Depienne C ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Muriel MP ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Acosta Lebrigio RF ( Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.); Gaussen M ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Noreau A ( Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.); Speziani F ( Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.); Dionne-Laporte A ( Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.); Deleuze JF ( Centre National de Genotypage, 91057 Evry, France.); Dion P ( Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.); Coutinho P ( UnIGENe and Centro de Genetica Preditiva e Preventiva, Institute for Molecular and Cellular Biology, 4050 Porto, Portugal.); Rouleau GA ( Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.); Zuchner S ( Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.); Brice A ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Stevanin G ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France); Darios F ( Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France) |
| Abstract | Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurological conditions. Their main pathogenic mechanisms are thought to involve alterations in endomembrane trafficking, mitochondrial function, and lipid metabolism. With a combination of whole-genome mapping and exome sequencing, we identified three mutations in REEP2 in two families with HSP: a missense variant (c.107T>A [p.Val36Glu]) that segregated in the heterozygous state in a family with autosomal-dominant inheritance and a missense change (c.215T>A [p.Phe72Tyr]) that segregated in trans with a splice site mutation (c.105+3G>T) in a family with autosomal-recessive transmission. REEP2 belongs to a family of proteins that shape the endoplasmic reticulum, an organelle that was altered in fibroblasts from an affected subject. In vitro, the p.Val36Glu variant in the autosomal-dominant family had a dominant-negative effect; it inhibited the normal binding of wild-type REEP2 to membranes. The missense substitution p.Phe72Tyr, in the recessive family, decreased the affinity of the mutant protein for membranes that, together with the splice site mutation, is expected to cause complete loss of REEP2 function. Our findings illustrate how dominant and recessive inheritance can be explained by the effects and nature of mutations in the same gene. They have also important implications for genetic diagnosis and counseling in clinical practice because of the association of various modes of inheritance to this new clinico-genetic entity. |
| ISSN | 00029297 |
| e-ISSN | 15376605 |
| DOI | 10.1016/j.ajhg.2013.12.005 |
| Journal | The American Journal of Human Genetics |
| Issue Number | 2 |
| Volume Number | 94 |
| Language | English |
| Publisher | Cell Press (on behalf of American Society of Human Genetics) |
| Publisher Date | 2014-02-06 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Membrane Proteins Genetics Spastic Paraplegia, Hereditary Amino Acid Sequence Animals Cos Cells Cercopithecus Aethiops Chromosome Mapping Exome Heterozygote Metabolism Molecular Sequence Data Mutation, Missense Pedigree Phenotype Pathology Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Human Genetics |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Genetics (clinical) |
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