We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more.
That zinc-deficiency is sufficient to produce a similar transformation in wild-type SOD1 implies that the wild-type and FALS-linked SOD1 mutants may trigger ALS by a common mechanism.
In our previous study, sequencing analyses identified one variant in the 3'-untranslated region (3'-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS.
The cellular functions that are impaired in motoneurons as a consequence of molecular alterations induced by the expression of FALS SOD1 converge on pathways that might be activated in sporadic ALS by other toxic factors.
Some cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), suggesting that oxidative damage may play a role in ALS pathogenesis.
These two mutants of SOD1 result in a FALS phenotype similar to that observed in patients with missense mutations in the SOD1 gene, establishing that exon 5 is not required for the novel toxic functions of mutant SOD1 associated with ALS.
The recognition of mutations in the copper/zinc superoxide dismutase (SOD1) gene in familial amyotrophic lateral sclerosis (FALS) has been a landmark in ALS research.
These studies show that, in addition to the previously demonstrated histological and electromyographic deficits, this transgenic mouse also presents changes in motor function reminiscent of the human disease, reinforcing and extending its validity as an animal model of familial amyotrophic lateral sclerosis (FALS) and allowing the investigation of novel drug treatment for ALS.
Familial amyotrophic lateral sclerosis (FALS) constitutes 5 to 10% of cases of ALS and, in most families, its inheritance is consistent with an autosomal dominant trait with age-dependent penetrance.