Identification of APTX disease-causing mutation in two unrelated Jordanian families with cerebellar ataxia and sensitivity to DNA damaging agents

PLoS One. 2020 Aug 4;15(8):e0236808. doi: 10.1371/journal.pone.0236808. eCollection 2020.


Background: Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive cerebellar ataxia, caused by mutations in the APTX gene. The disease is characterized by early-onset cerebellar ataxia, oculomotor apraxia and severe axonal polyneuropathy. The aim of this study was to detect the disease-causing variants in two unrelated consanguineous Jordanian families with cerebellar ataxia using whole exome sequencing (WES), and to correlate the identified mutation(s) with the clinical and cellular phenotypes.

Methods: WES was performed in three affected individuals and segregation analysis of p.W279* APTX candidate variant was performed. Expression levels of APTX were measured in patients' skin fibroblasts and peripheral blood mononuclear cells, followed by western blot analysis in skin fibroblasts. Genotoxicity assay was performed to detect the sensitivity of APTX mutated cells to H2O2, MMC, MMS and etoposide.

Results: A recurrent homozygous nonsense variant in APTX gene (c.837G>A, p.W279*) was revealed in all affected individuals. qRT-PCR showed normal APTX levels in peripheral blood and lower levels in fibroblast cells. However, western blot showed the absence of APTX protein in patients' skin fibroblasts. Significant hypersensitivity to H2O2, MMC and etoposide and lack of sensitivity to MMS were noted.

Conclusions: This is the first study to report the identification of a nonsense variant in the APTX gene (c.837G>A; p.W279*) in AOA1 patients within the Jordanian population. This study confirmed the need of WES to assist in the diagnosis of cerebellar ataxia and it emphasizes the importance of studying the pathophysiology of the APTX gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cerebellar Ataxia / genetics*
  • Child
  • Child, Preschool
  • Codon, Nonsense*
  • Consanguinity
  • DNA / drug effects
  • DNA Damage*
  • DNA-Binding Proteins / genetics*
  • Exome Sequencing
  • Female
  • Humans
  • Male
  • Mutagens / pharmacology
  • Nuclear Proteins / genetics*


  • APTX protein, human
  • Codon, Nonsense
  • DNA-Binding Proteins
  • Mutagens
  • Nuclear Proteins
  • DNA

Grants and funding

This work was supported by the deanship of scientific research, University of Jordan, grant (2018- 2017/2). The funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of research materials.