SETX – Amyotrophic Lateral Sclerosis type 4

SETX variants cause an autosomal dominant juvenile motor neuron disease, Amyotrophic Lateral Sclerosis type 4, characterized by slowly progressive limb amyotrophy and pyramidal tract signs. Linkage analysis in an 11-generation kindred mapped the ALS4 locus to chromosome 9q34 (LOD 18.8) (PMID:9497266). Subsequent sequencing identified a recurrent c.1166T>C (p.Leu389Ser) missense variant in 31 of 32 patients and a c.1153G>A (p.Glu385Lys) change in one patient (PMID:31957062).

Inheritance is autosomal dominant with segregation of p.Leu389Ser in multiple affected relatives across the original pedigree (PMID:9497266). Clinical evaluation of 32 individuals confirmed slowly progressive amyotrophy (HP:0003677) and abnormal pyramidal signs (HP:0007256) in all probands (PMID:31957062).

Functional assays in patient fibroblasts and induced motor neurons demonstrated that both p.Leu389Ser and p.Glu385Lys variants reduce R-loop accumulation, implicating a toxic gain-of-function effect on Senataxin helicase activity (PMID:31957062). Yeast two-hybrid screens and co-immunoprecipitation revealed mutant-specific interactions with a BCYRN1-encoded peptide and ubiquitin-SUMO pathway enzymes, highlighting aberrant protein associations in ALS4 pathogenesis (PMID:24244371).

Allele-specific silencing using siRNA targeting the c.1166T>C transcript selectively reduced mutant Senataxin levels and restored R-loop homeostasis in patient cells, supporting RNA interference as a potential therapeutic strategy (PMID:39416141). Mouse and cellular models corroborate a dominant gain-of-function mechanism whereby mutant SETX disrupts transcription termination and genome stability.

Collectively, these data fulfill strong ClinGen criteria: a linked multi-generation pedigree, >30 affected individuals, recurrent pathogenic variants, segregation, and concordant functional evidence. Key Take-home: Testing for the recurrent p.Leu389Ser variant in SETX enables definitive diagnosis and informs the development of allele-specific therapies in ALS4.

References

• American journal of human genetics • 1998 • Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34 PMID:9497266
• Annals of neurology • 2020 • Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4 PMID:31957062
• PloS one • 2013 • Protein interaction analysis of senataxin and the ALS4 L389S mutant yields insights into senataxin post-translational modification and uncovers mutant-specific binding with a brain cytoplasmic RNA-encoded peptide PMID:24244371
• bioRxiv : the preprint server for biology • 2024 • Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4 PMID:39416141

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