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<p>Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic <i>SETX</i> gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16&#xa0;kb on chromosome 9 (chr9:132,295,852–132,311,876), suggesting a deletion encompassing 5 exons of the <i>SETX</i> gene (exons 11–15, NM_015046.7) was observed. This homozygous <i>SETX</i> (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the <i>SETX</i> gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.</p>

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Ataxia and oculomotor apraxia caused by a large-scale deletion in the senataxin gene

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月20日

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  • Joanna M. Rusecka,
  • Biruta Kierdaszuk,
  • Iwona Stępniak,
  • Małgorzata Rydzanicz,
  • Piotr Stawiński,
  • Tomasz Gambin,
  • Damian Loska,
  • Magdalena M. Kacprzak,
  • Magdalena Kaliszewska,
  • Dorota Piekutowska-Abramczuk,
  • Anna M. Kamińska,
  • Ewa Pronicka,
  • Ewa Bartnik,
  • Anna Kostera-Pruszczyk,
  • Rafał Płoski,
  • Agnieszka Sobczyńska-Tomaszewska,
  • Katarzyna Tońska

摘要

Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic SETX gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16 kb on chromosome 9 (chr9:132,295,852–132,311,876), suggesting a deletion encompassing 5 exons of the SETX gene (exons 11–15, NM_015046.7) was observed. This homozygous SETX (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the SETX gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.