title: Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia.
abstract: 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.
authors: Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California 90095-1732, USA.
authors: Kotoka
authors: K
authors: Nakamura
authors: Liutao
authors: L
authors: Du
authors: Rashmi
authors: R
authors: Tunuguntla
authors: Francesca
authors: F
authors: Fike
authors: Simona
authors: S
authors: Cavalieri
authors: Tomohiro
authors: T
authors: Morio
authors: Shuki
authors: S
authors: Mizutani
authors: Alfredo
authors: A
authors: Brusco
authors: Richard A
authors: RA
authors: Gatti
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology / Q000627:therapeutic use; D044466:Asian People; D001260:Ataxia Telangiectasia / Q000188:drug therapy / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000819:agonists / Q000235:genetics*; D002460:Cell Line; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics*; D005091:Exons; D016368:Frameshift Mutation; D005839:Gentamicins / Q000494:pharmacology / Q000627:therapeutic use; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D060172:Morpholinos / Q000494:pharmacology / Q000627:therapeutic use; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012326:RNA Splicing; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000819:agonists / Q000235:genetics*
chemical_list: D000617:Aminoglycosides; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D005839:Gentamicins; D060172:Morpholinos; D020319:Oligodeoxyribonucleotides, Antisense; D025521:Tumor Suppressor Proteins; C010680:antibiotic G 418; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases