Unique Ataxia-Oculomotor Apraxia 2 (AOA2) in Israel with Novel Variants, Atypical Late Presentation, and Possible Identification of a Poison Exon

Penina Ponger*, Alina Kurolap, Israela Lerer, Judith Dagan, Chofit Chai Gadot, Adi Mory, Yael Wilnai, Nino Oniashvili, Nir Giladi, Tanya Gurevich, Vardiella Meiner, Alexander Lossos, Hagit Baris Feldman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


AOA2 is a rare progressive adolescent-onset disease characterised by cerebellar vermis atrophy, peripheral neuropathy and elevated serum alpha-fetoprotein (AFP) caused by pathogenic bi-allelic variants in SETX, encoding senataxin, involved in DNA repair and RNA maturation. Sanger sequencing of genomic DNA, co-segregation and oxidative stress functional studies were performed in Family 1. Trio whole-exome sequencing (WES), followed by SETX RNA and qRT-PCR analysis, were performed in Family 2. Sanger sequencing in Family 1 revealed two novel in-frame SETX deletion and duplication variants in trans (c.7009_7011del; p.Val2337del and c.7369_7371dup; p.His2457dup). Patients had increased induced chromosomal aberrations at baseline and following exposure to higher mitomycin-C concentration and increased sensitivity to oxidative stress at the lower mitomycin-C concentration in cell viability test. Trio WES in Family 2 revealed two novel SETX variants in trans, a nonsense variant (c.568C > T; p.Gln190*), and a deep intronic variant (c.5549-107A > G). Intronic variant analysis and SETX mRNA expression revealed activation of a cryptic exon introducing a premature stop codon (p.Met1850Lysfs*18) and resulting in aberrant splicing, as shown by qRT-PCR analysis, thus leading to higher levels of cryptic exon activation. Along with a second deleterious allele, this variant leads to low levels of SETX mRNA and disease manifestations. Our report expands the phenotypic spectrum of AOA2. Results provide initial support for the hypomorphic nature of the novel in-frame deletion and duplication variants in Family 1. Deep-intronic variant analysis of Family 2 variants potentially reveals a previously undescribed poison exon in the SETX gene, which may contribute to tailored therapy development.

Original languageEnglish
Pages (from-to)1715-1723
Number of pages9
JournalJournal of Molecular Neuroscience
Issue number8
StatePublished - Aug 2022


  • AOA2
  • Ataxia-oculomotor apraxia 2
  • Poison exon
  • SCAN2
  • SETX
  • Senataxin
  • Spinocerebellar ataxia with axonal neuropathy 2


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