TY - JOUR
T1 - I112M SOD1 mutation causes ALS with rapid progression and reduced penetrance in four Mediterranean families
AU - Gamez, Josep
AU - Caponnetto, Claudia
AU - Ferrera, Loretta
AU - Syriani, Enrique
AU - Marini, Valeria
AU - Morales, Miguel
AU - Bordo, Domenico
AU - Pirro, Cristina
AU - Garre, Cecilia
AU - Origone, Paola
PY - 2011/1
Y1 - 2011/1
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - haplotype
KW - I112M mutation
KW - phenotype-genotype correlation
KW - SOD1
UR - http://www.scopus.com/inward/record.url?scp=79251611966&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79251611966&partnerID=8YFLogxK
U2 - 10.3109/17482968.2010.487906
DO - 10.3109/17482968.2010.487906
M3 - Article
C2 - 20515426
AN - SCOPUS:79251611966
VL - 12
SP - 70
EP - 75
JO - Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders
JF - Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders
SN - 1466-0822
IS - 1
ER -