I112M SOD1 mutation causes ALS with rapid progression and reduced penetrance in four Mediterranean families.
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.
Gamez
Josep
J
Department of Neurology, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain.
Caponnetto
Claudia
C
Ferrera
Loretta
L
Syriani
Enrique
E
Marini
Valeria
V
Morales
Miguel
M
Bordo
Domenico
D
Pirro
Cristina
C
Garre
Cecilia
C
Origone
Paola
P
D000328:Adult; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D018450:Disease Progression; D018703:Founder Effect; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D017354:Point Mutation; D011487:Protein Conformation; D055550:Protein Stability; D012802:Sicily / Q000453:epidemiology; D013030:Spain / Q000453:epidemiology; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1