Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia

Hum Mutat. 2012 Jan;33(1):198-208. doi: 10.1002/humu.21632. Epub 2011 Nov 9.


A recent challenge for investigators studying the progressive neurological disease ataxia-telangiectasia (A-T) is to identify mutations whose effects might be alleviated by mutation-targeted therapies. We studied ATM mutations in eight families of Japanese A-T patients (JPAT) and were able to identify all 16 mutations. The probands were compound heterozygotes in seven families, and one (JPAT2) was homozygous for a frameshift mutation. All mutations--four frameshift, two nonsense, four large genomic deletions, and six affecting splicing--were novel except for c.748C>T found in family JPAT6 and c.2639-384A>G found in family JPAT11/12. Using an established lymphoblastoid cell line (LCL) of patient JPAT11, ATM protein was restored to levels approaching wild type by exposure to an antisense morpholino oligonucleotide designed to correct a pseudoexon splicing mutation. In addition, in an LCL from patient JPAT8/9, a heterozygous carrier of a nonsense mutation, ATM levels could also be partially restored by exposure to readthrough compounds (RTCs): an aminoglycoside, G418, and a novel small molecule identified in our laboratory, RTC13. Taken together, our results suggest that screening and functional characterization of the various sorts of mutations affecting the ATM gene can lead to better identification of A-T patients who are most likely to benefit from rapidly developing mutation-targeted therapeutic technologies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglycosides / pharmacology
  • Aminoglycosides / therapeutic use
  • Asians
  • Ataxia Telangiectasia / drug therapy
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Cell Cycle Proteins / agonists
  • Cell Cycle Proteins / genetics*
  • Cell Line
  • Codon, Nonsense*
  • DNA Mutational Analysis
  • DNA-Binding Proteins / agonists
  • DNA-Binding Proteins / genetics*
  • Exons
  • Frameshift Mutation*
  • Gentamicins / pharmacology
  • Gentamicins / therapeutic use
  • Heterozygote
  • Humans
  • Molecular Sequence Data
  • Molecular Targeted Therapy
  • Morpholinos / pharmacology
  • Morpholinos / therapeutic use
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Oligodeoxyribonucleotides, Antisense / therapeutic use
  • Pedigree
  • Protein Serine-Threonine Kinases / genetics*
  • RNA Splicing
  • Sequence Deletion*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Tumor Suppressor Proteins / agonists
  • Tumor Suppressor Proteins / genetics*


  • Aminoglycosides
  • Cell Cycle Proteins
  • Codon, Nonsense
  • DNA-Binding Proteins
  • Gentamicins
  • Morpholinos
  • Oligodeoxyribonucleotides, Antisense
  • Tumor Suppressor Proteins
  • antibiotic G 418
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases