I112M SOD1 mutation causes ALS with rapid progression and reduced penetrance in four Mediterranean families
| Autor: | Claudia Caponnetto, Enrique Syriani, Cecilia Garrè, Loretta Ferrera, Domenico Bordo, Valeria Marini, Josep Gamez, Miguel Morales, Paola Origone, Cristina Pirro |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Adult
Models Molecular Genotype Protein Conformation Mutation Missense Penetrance Biology Homology (biology) Structure-Activity Relationship Superoxide Dismutase-1 amyotrophic lateral sclerosis haplotype phenotype-genotype correlation sod1 i112m mutation medicine Humans Point Mutation Amyotrophic lateral sclerosis Sicily Gene Genetics Protein Stability Superoxide Dismutase Amyotrophic Lateral Sclerosis Haplotype General Medicine Middle Aged medicine.disease Phenotype Founder Effect Pedigree Amino Acid Substitution Haplotypes Neurology Spain Genetic marker Disease Progression Neurology (clinical) Founder effect |
| Popis: | We evaluated a possible genotype-phenotype correlation and looked for a founder effect in four Mediterranean families carrying the I112M SOD1 mutation. The structural characteristics of the mutated protein were also analysed. Clinical data of FALS subjects from four families were evaluated. Mutational analysis of the SOD1 gene was carried out by direct sequencing. A haplotype study was carried out using 11 polymorphic markers flanking the SOD1 gene. Structural analysis was performed by means of homology modelling and molecular graphics methods. The clinical pattern of 17 FALS patients was characterized by prevalent spinal onset, mean age at onset of 47.1 years and mean duration of 20.7 months. Several obligate carriers were observed. These findings indicate that the I112M mutation is consistently associated with a uniform, fast-progressing phenotype with reduced penetrance of the disease. The haplotype analysis did not show a common haplotype among the Spanish families and the Italian family; however, a possible common founder could be hypothesized for Spanish families. From a structural viewpoint, mutation at codon 112 seems to confer a severe phenotype, probably related to altered protein functionality. |
| Databáze: | OpenAIRE |
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