Identification of Six Novel SOD1 Gene Mutations in Familial Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SODl) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn 2+ binding sites, a region where no previous SODl mutations have been found. Our data increase the number of different SODl mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein. RESUME: Identification de six nouvelles mutations dans le gene SODl de patients atteints de laSclerose Laterale Amyotrophique. La Sclerose Laterale Amyotrophique (SLA) est une maladie neurodegenerative caracterisee par la mort prematuree des motoneurones. Dans 10% des cas, la SLA est herediataire et caracterisee par une transmission autosomique dominante (SLAF). II a ete prouve que des mutations dans le gene codant pour la Cu/Zn superoxyde dismutase (SODl) sont responsables de 15% des cas de SLAF. L'analyse des regions condantes du gene SODl de 70 patients nonapparentes atteints de SLAF nous a permis de decouvrir 10 mutations dont six sont nouvelles. Fait inatendu, nous avons trouve la premiere mutation dans l'exon 3 qui code pour la majeure partie du site actif et des sites de fixation du Zn 2+ . De plus, nous avons identife une deuxieme mutation recessive. Cette etude porte le nombre de mutations SODl differentes a 55 impliquant 37 codons, une fraction significative de cette proteine relativement petite constitute de 154 acides amines.

Abnormally high levels of SOD1 mRNA in a patient with amyotrophic lateral sclerosis

“…A similar type of mutation has been documented by Boukaftane et al, 1 who found a deletion in intron 4 of three nucleotides 30-bp downstream of the exon-intron splice junction in a FALS patient, but they did not investigate the mRNA levels.…”

Identification of two novel mutations in the Cu/Zn superoxide dismutase gene with familial amyotrophic lateral sclerosis: mass spectrometric and genomic analyses

“…Segregation of the mutations could not be confirmed in the families presented here, because of the death of the affected members. The conservation of Asp at codon 101 and Gly at codon 141 among various species [25] suggests that these amino acids are essential for the proper function of SOD1.…”

Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene

“…Thus, at present 119 (108 + 11) SOD1 mutations have been associated with ALS (ALSOD) and are presumed to be causative, but many are private mutations found in single families and validation is lacking [9,[19][20][21][22][23][24]. The 119 mutations are scattered all over the molecule with predilection for exons 4 and 5.…”

“…In heavily inbred families, three patients homozygous for the L84F, N86S, and L126S mutations have been reported, whereas other patients have been heterozygous [20,34,35]. Tragically, when these mutations appear in homozygous form, the resulting disease has sudden onset and extremely fast progression to death.…”