REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction
| Autor: | Julie Pilliod, Estelle Fedirko, Imed Feki, Didier Lacombe, Alexandra Durr, Perrine Charles, Cyril Goizet, Marie-Laure Martin-Negrier, Alexis Brice, Giovanni Benard, Sylvie Forlani, Eric LeGuern, Jean-François Pinel, Elisabeth Ollagnon-Roman, Rodrigue Rossignol, Giovanni Stevanin, Didier Hannequin, Annick Toutain, Stanislas Lyonnet, J. Yaouanq, Amir Boukhris, Emeline Mundwiller, Bertrand Fontaine, Anne-Marie Ouvrard-Hernandez, Cécile Cazeneuve, Christel Depienne, G. Sole, Isabelle Coupry, Christelle Dussert |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Mutation rate Adolescent Hereditary spastic paraplegia Biology Mitochondrion Exon Young Adult Mutation Rate Genetics medicine Humans Multiplex ligation-dependent probe amplification Child Muscle Skeletal Gene Genetics (clinical) Aged Sequence Deletion Cerebellar ataxia Base Sequence Spastic Paraplegia Hereditary Infant Newborn Infant Membrane Transport Proteins Middle Aged medicine.disease Phenotype Mitochondria Pedigree Child Preschool Mutation Female medicine.symptom Energy Metabolism |
| Zdroj: | Human mutation. 32(10) |
| ISSN: | 1098-1004 |
| Popis: | Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with a pure dominant HSP, SPG31. We sequenced all exons of REEP1 and searched for rearrangements by multiplex ligation-dependent probe amplification (MLPA) in a large panel of 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), with either pure (n = 102) or complicated (n = 73) forms of the disease, after exclusion of other known HSP genes. We identified 12 different heterozygous mutations, including two exon deletions, associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but nine had a complex phenotype associating axonal peripheral neuropathy (= 5/11 patients) including a Silver-like syndrome in one patient, and less frequently cerebellar ataxia, tremor, dementia. Interestingly, we evidenced abnormal mitochondrial network organization in fibroblasts of one patient in addition to defective mitochondrial energy production in both fibroblasts and muscle, but whether these anomalies are directly or indirectly related to the mutations remains uncertain. Hum Mutat 32:1118–1127, 2011. ©2011 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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