Top

Published in:

Open Access 01-12-2009

Aberrant Splicing of the Senataxin Gene in a Patient with Ataxia with Oculomotor Apraxia Type 2

Authors: Brent L. Fogel, Ji Yong Lee, Susan Perlman

Published in: The Cerebellum | Issue 4/2009

Abstract

Ataxia with oculomotor apraxia type 2 (AOA2) is caused by a diversity of mutations within the coding region of the senataxin gene. Recently, rare noncoding senataxin mutations affecting RNA processing have been identified in AOA2. Here, we report the case of an 18-year-old woman, with classic clinical features of AOA2, who was found to harbor a mutation within senataxin intron 16. This mutation disrupts the local 5′ splice site architecture via a novel intronic frameshift mechanism, causing skipping of exon 16 with predicted disruption of the conserved DNA/RNA helicase domain. RNA processing mutations expand the growing complexity of pathogenic senataxin mutations.

Moreira MC, Klur S, Watanabe M, Nemeth AH, Le Ber I, Moniz JC et al (2004) Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 36:225–227CrossRefPubMed

Le Ber I, Bouslam N, Rivaud-Pechoux S, Guimaraes J, Benomar A, Chamayou C et al (2004) Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. Brain 127:759–767CrossRefPubMed

Duquette A, Roddier K, McNabb-Baltar J, Gosselin I, St-Denis A, Dicaire MJ et al (2005) Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy. Ann Neurol 57:408–414CrossRefPubMed

Fogel BL, Perlman S (2007) Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol 6:245–257CrossRefPubMed

Criscuolo C, Chessa L, Di Giandomenico S, Mancini P, Sacca F, Grieco GS et al (2006) Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology 66:1207–1210CrossRefPubMed

Anheim M, Fleury MC, Franques J, Moreira MC, Delaunoy JP, Stoppa-Lyonnet D et al (2008) Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families. Arch Neurol 65:958–962CrossRefPubMed

Tazir M, Ali-Pacha L, M’Zahem A, Delaunoy JP, Fritsch M, Nouioua S et al (2009) Ataxia with oculomotor apraxia type 2: a clinical and genetic study of 19 patients. J Neurol Sci 278:77–81CrossRefPubMed

Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J et al (2004) DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 74:1128–1135CrossRefPubMed

Chen YZ, Hashemi SH, Anderson SK, Huang Y, Moreira MC, Lynch DR et al (2006) Senataxin, the yeast Sen1p orthologue: characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease. Neurobiol Dis 23:97–108CrossRefPubMed

10.

Zhao ZH, Chen WZ, Wu ZY, Wang N, Zhao GX, Chen WJ et al (2008) A novel mutation in the senataxin gene identified in a Chinese patient with sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10(2):118–122CrossRef

11.

Asaka T, Yokoji H, Ito J, Yamaguchi K, Matsushima A (2006) Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX. Neurology 66:1580–1581CrossRefPubMed

12.

Fogel BL, Perlman S (2006) Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2. Neurology 67:2083–2084CrossRefPubMed

13.

Lynch DR, Braastad CD, Nagan N (2007) Ovarian failure in ataxia with oculomotor apraxia type 2. Am J Med Genet 143A:1775–1777CrossRefPubMed

14.

Arning L, Schols L, Cin H, Souquet M, Epplen JT, Timmann D (2008) Identification and characterisation of a large Senataxin (SETX) gene duplication in ataxia with ocular apraxia type 2 (AOA2). Neurogenetics 9:295–299CrossRefPubMed

15.

Nicolaou P, Georghiou A, Votsi C, Middleton LT, Zamba-Papanicolaou E, Christodoulou K (2008) A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia. BMC Med Genet 9:28CrossRefPubMed

16.

Schols L, Arning L, Schule R, Epplen JT, Timmann D (2008) “Pseudodominant inheritance” of ataxia with ocular apraxia type 2 (AOA2). J Neurol 255:495–501CrossRefPubMed

17.

Suraweera A, Becherel OJ, Chen P, Rundle N, Woods R, Nakamura J et al (2007) Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage. J Cell Biol 177:969–979CrossRefPubMed

18.

Koscielny G, Le Texier V, Gopalakrishnan C, Kumanduri V, Riethoven JJ, Nardone F et al (2009) ASTD: the alternative splicing and transcript diversity database. Genomics 93:213–220CrossRefPubMed

19.

Ursic D, Chinchilla K, Finkel JS, Culbertson MR (2004) Multiple protein/protein and protein/RNA interactions suggest roles for yeast DNA/RNA helicase Sen1p in transcription, transcription-coupled DNA repair and RNA processing. Nucleic Acids Res 32:2441–2452CrossRefPubMed

20.

Korzinov OM, Astakhova TV, Vlasov PK, Roitberg MA (2008) Statistical analysis of DNA sequences nearby splicing sites. Mol Biol (Mosk) 42:150–162

21.

Goodarzi MO, Azziz R (2006) Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab 20:193–205CrossRefPubMed

Title: Aberrant Splicing of the Senataxin Gene in a Patient with Ataxia with Oculomotor Apraxia Type 2
Authors: Brent L. Fogel
Ji Yong Lee
Susan Perlman
Publication date: 01-12-2009
Publisher: Springer-Verlag
Published in: The Cerebellum / Issue 4/2009
Print ISSN: 1473-4222
Electronic ISSN: 1473-4230
DOI: https://doi.org/10.1007/s12311-009-0130-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Aberrant Splicing of the Senataxin Gene in a Patient with Ataxia with Oculomotor Apraxia Type 2

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2009

Cerebellar Disorders—At the Crossroad of Molecular Pathways and Diagnosis

A Rare Variant of Persistent Trigeminal Artery: Cavernous Carotid-Cerebellar Artery Anastomosis—A Case Report and a Systematic Review

Paraneoplastic Cerebellar Degeneration Mimicking Acute Post-Infectious Cerebellitis

Persistent Adeno-associated Virus 2 and Parvovirus B19 Sequences in Post-mortem Human Cerebellum

Role of PACAP in Controlling Granule Cell Migration

Increased Concentrations of Nerve Growth Factor and Brain-Derived Neurotrophic Factor in the Rat Cerebellum After Exposure to Environmental Enrichment