Unique Ataxia-Oculomotor Apraxia 2 (AOA2) in Israel with Novel Variants, Atypical Late Presentation, and Possible Identification of a Poison Exon.
AOA2
Ataxia-oculomotor apraxia 2
Poison exon
SCAN2
SETX
Senataxin
Spinocerebellar ataxia with axonal neuropathy 2
Journal
Journal of molecular neuroscience : MN
ISSN: 1559-1166
Titre abrégé: J Mol Neurosci
Pays: United States
ID NLM: 9002991
Informations de publication
Date de publication:
Aug 2022
Aug 2022
Historique:
received:
11
04
2022
accepted:
27
05
2022
pubmed:
9
6
2022
medline:
17
8
2022
entrez:
8
6
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35676594
doi: 10.1007/s12031-022-02035-5
pii: 10.1007/s12031-022-02035-5
doi:
Substances chimiques
Codon, Nonsense
0
Multifunctional Enzymes
0
Poisons
0
Mitomycin
50SG953SK6
SETX protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1715-1723Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Airoldi G, Guidarelli A, Cantoni O et al (2010) Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin. Neurogenetics. https://doi.org/10.1007/s10048-009-0206-0
doi: 10.1007/s10048-009-0206-0
pubmed: 19593598
Algahtani H, Shirah B, Algahtani R et al (2018) Ataxia with ocular apraxia type 2 not responding to 4-aminopyridine: a rare mutation in the SETX gene in a Saudi patient. Intractable Rare Dis Res. https://doi.org/10.5582/irdr.2018.01107
doi: 10.5582/irdr.2018.01107
pubmed: 30560021
pmcid: 6290838
Anheim M, Monga B, Fleury M et al (2009) Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain. https://doi.org/10.1093/brain/awp211
doi: 10.1093/brain/awp211
pubmed: 19696032
Arning L, Schöls L, Cin H et al (2008) Identification and characterisation of a large senataxin (SETX) gene duplication in ataxia with ocular apraxia type 2 (AOA2). Neurogenetics. https://doi.org/10.1007/s10048-008-0139-z
doi: 10.1007/s10048-008-0139-z
pubmed: 18663494
Cartegni L, Wang J, Zhu Z et al (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res. https://doi.org/10.1093/nar/gkg616
doi: 10.1093/nar/gkg616
pubmed: 12824367
pmcid: 169022
Carvill GL, Mefford HC (2020) Poison exons in neurodevelopment and disease. Curr Opin Genet Dev. https://doi.org/10.1016/j.gde.2020.05.030
doi: 10.1016/j.gde.2020.05.030
pubmed: 32615329
pmcid: 8042789
Cohen S, Puget N, Lin Y et al (2018) Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations. Nat Commun. https://doi.org/10.1038/s41467-018-02894-w
doi: 10.1038/s41467-018-02894-w
pubmed: 30560939
pmcid: 6299136
Criscuolo C, Chessa L, Di Giandomenico S et al (2006) Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology. https://doi.org/10.1212/01.wnl.0000208402.10512.4a
doi: 10.1212/01.wnl.0000208402.10512.4a
pubmed: 16636238
Datta N, Hohler A (2013) A new SETX mutation producing AOA2 in two siblings. Int J Neurosci. https://doi.org/10.3109/00207454.2013.787616
doi: 10.3109/00207454.2013.787616
pubmed: 23566282
Desmet FO, Hamroun D, Lalande M et al (2009) Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. https://doi.org/10.1093/nar/gkg616
doi: 10.1093/nar/gkg616
pubmed: 19339519
pmcid: 2685110
Fogel B, Cho E, Wahnich A et al (2014) Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2. Hum Mol Genet. https://doi.org/10.1093/hmg/ddu190
doi: 10.1093/hmg/ddu190
pubmed: 24760770
pmcid: 4140459
Gazulla J, Benavente I, Pérez López-Fraile I et al (2010) Sensory neuronopathy in ataxia with oculomotor apraxia type 2. J Neurol Sci. https://doi.org/10.1016/j.jns.2010.09.004
doi: 10.1016/j.jns.2010.09.004
pubmed: 20869730
Grunseich C, Wang I, Watts J et al (2018) Senataxin mutation reveals how r-loops promote transcription by blocking DNA methylation at gene promoters. Mol Cell. https://doi.org/10.1016/j.molcel.2017.12.030
doi: 10.1016/j.molcel.2017.12.030
pubmed: 29395064
pmcid: 5815878
Jaganathan K, Panagiotopoulou SK, McRae JF et al (2019) Predicting splicing from primary sequence with deep learning. Cell. https://doi.org/10.1016/j.cell.2018.12.015
doi: 10.1016/j.cell.2018.12.015
pubmed: 30661751
Kanagaraj R, Mitter R, Kantidakis T et al (2022) Integrated genome and transcriptome analyses reveal the mechanism of genome instability in ataxia with oculomotor apraxia 2. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.2114314119
doi: 10.1073/pnas.2114314119
pubmed: 35042798
pmcid: 8795503
Lavin M, Yeo A, Becherel O (2013) Senataxin protects the genome, implications for neurodegeneration and other abnormalities. Rare Diseases. https://doi.org/10.4161/rdis.25230
doi: 10.4161/rdis.25230
pubmed: 25003001
pmcid: 3927485
Motokura E, Yamashita T, Takahashi Y et al (2017) An AOA2 patient with a novel compound heterozygous SETX frame shift mutations. J Neurol Sci. https://doi.org/10.1016/j.jns.2016.11.074
doi: 10.1016/j.jns.2016.11.074
pubmed: 28131200
Oostra A, Nieuwint A, Joenje H et al (2012) Diagnosis of Fanconi anemia: chromosomal breakage analysis. Anemia. https://doi.org/10.1155/2012/238731
doi: 10.1155/2012/238731
pubmed: 22693659
pmcid: 3368163
Pera J, Lechner S, Biskup S et al (2015) Two novel mutations of the SETX gene and ataxia with oculomotor apraxia type 2. Clin Neurol Neurosurg. https://doi.org/10.1016/j.clineuro.2014.10.024
doi: 10.1016/j.clineuro.2014.10.024
pubmed: 25462094
Rexach J, Lee H, Martinez-Agosto JA et al (2019) Clinical application of next-generation sequencing to the practice of neurology. Lancet Neurol. https://doi.org/10.1016/S1474-4422(19)30033-X
doi: 10.1016/S1474-4422(19)30033-X
pubmed: 30981321
pmcid: 7055532
Screaton GR, Cáceres JF, Mayeda A et al (1995) Identification and characterization of three members of the human SR family of pre-mRNA splicing factors. EMBO J 14(17):4336–49
Szpisjak L, Obal I, Engelhardt J et al (2016) A novel SETX gene mutation producing ataxia with oculomotor apraxia type 2. Acta Neurol Belg. https://doi.org/10.1007/s13760-015-0569-y
doi: 10.1007/s13760-015-0569-y
pubmed: 26811093
Ta-Shma A, Zhang K, Salimova E et al (2017) Congenital valvular defects associated with deleterious mutations in the. J Med Genet. https://doi.org/10.1136/jmedgenet-2016-10425923
doi: 10.1136/jmedgenet-2016-10425923
pubmed: 27799408
Vantaggiato C, Cantoni O, Guidarelli A et al (2014) Novel SETX variants in a patient with ataxia, neuropathy, and oculomotor apraxia are associated with normal sensitivity to oxidative DNA damaging agents. Brain Dev. https://doi.org/10.1016/j.braindev.2013.10.003
doi: 10.1016/j.braindev.2013.10.003
pubmed: 24183476
Yaron Y, Ofen Glassner V, Mory A et al (2022) Exome sequencing as a first-tier test for fetuses with severe central nervous system structural anomalies. Ultrasound Obstet Gynecol. https://doi.org/10.1002/uog.24885
doi: 10.1002/uog.24885
pubmed: 35229910
pmcid: 9328397