Makito Hirano1, Ryusuke Matsumura2, Yusaku Nakamura3, Kazumasa Saigoh4, Hikaru Sakamoto3, Shuichi Ueno3, Hiroya Inoue2, Susumu Kusunoki4. 1. Department of Neurology, Sakai Hospital Kindai University Faculty of Medicine, Japan; Department of Neurology, Kindai University Faculty of Medicine, Japan. Electronic address: mahirano-neuro@umin.ac.jp. 2. Department of Neurology, National Hospital Organization Nara Medical Center, Japan. 3. Department of Neurology, Sakai Hospital Kindai University Faculty of Medicine, Japan. 4. Department of Neurology, Kindai University Faculty of Medicine, Japan.
Abstract
INTRODUCTION: Early onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia 1 (AOA1) is an autosomal recessive disorder caused by mutations in the APTX gene. In contrast to the recent progress on the molecular mechanism of aprataxin in DNA repair, the genotype and phenotype correlation has not been fully established. A previous study demonstrated that patients with truncation mutations had earlier onset of disease than those with missense mutations METHODS: Genomic DNA analysis was performed in a consanguineous family with relatively late-onset EAOH/AOA1. In addition, mRNA and protein analyses were performed. RESULTS: The proband of the family had a homozygous two-base deletion in the middle of exon 3. Reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of mRNA revealed an aberrantly spliced mRNA with a cryptic splice site located four bases upstream of the deletion site. The newly identified mRNA retained a frameshift mutation and encoded a truncated protein. Immunoblot analysis did not detect the truncated protein in the patient's fibroblasts, possibly because it was unstable. CONCLUSIONS: Although patients with truncation mutations had an earlier onset of disease, our findings suggest that patients with a truncation mutation resulting in an undetectable protein level can also have a later onset of disease.
INTRODUCTION: Early onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia 1 (AOA1) is an autosomal recessive disorder caused by mutations in the APTX gene. In contrast to the recent progress on the molecular mechanism of aprataxin in DNA repair, the genotype and phenotype correlation has not been fully established. A previous study demonstrated that patients with truncation mutations had earlier onset of disease than those with missense mutations METHODS: Genomic DNA analysis was performed in a consanguineous family with relatively late-onset EAOH/AOA1. In addition, mRNA and protein analyses were performed. RESULTS: The proband of the family had a homozygous two-base deletion in the middle of exon 3. Reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of mRNA revealed an aberrantly spliced mRNA with a cryptic splice site located four bases upstream of the deletion site. The newly identified mRNA retained a frameshift mutation and encoded a truncated protein. Immunoblot analysis did not detect the truncated protein in the patient's fibroblasts, possibly because it was unstable. CONCLUSIONS: Although patients with truncation mutations had an earlier onset of disease, our findings suggest that patients with a truncation mutation resulting in an undetectable protein level can also have a later onset of disease.