The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.
The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.
Moreira
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MC
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis-Pasteur, Illkirch, C.U. de Strasbourg, France.
Barbot
C
C
Tachi
N
N
Kozuka
N
N
Uchida
E
E
Gibson
T
T
Mendonça
P
P
Costa
M
M
Barros
J
J
Yanagisawa
T
T
Watanabe
M
M
Ikeda
Y
Y
Aoki
M
M
Nagata
T
T
Coutinho
P
P
Sequeiros
J
J
Koenig
M
M
D000595:Amino Acid Sequence; D001072:Apraxias / Q000150:complications / Q000235:genetics*; D001259:Ataxia / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D009801:Oculomotor Muscles / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D016335:Zinc Fingers
C438188:APTX protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins