Highlights
- •We found a novel homozygous two-base deletion in the APTX gene.
- •An aberrantly spliced mRNA was created with a cryptic splice site.
- •The aberrant mRNA retained a frameshift mutation and encoded a truncated protein.
- •Immunoblotting did not detect the truncated protein.
- •Patients with a truncation mutation can also have a later onset of ataxia.
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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of the Neurological SciencesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.Nat. Genet. 2001; 29: 184-188
- The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.Nat. Genet. 2001; 29: 189-193
- Loss of function mechanism in aprataxin-related early-onset ataxia.Biochem. Biophys. Res. Commun. 2004; 322: 380-386
- ALADINI482S causes selective failure of nuclear protein import and hypersensitivity to oxidative stress in triple A syndrome.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 2298-2303
- Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress.Biochem. Biophys. Res. Commun. 2008; 374: 631-634
- DNA single-strand break repair is impaired in aprataxin-related ataxia.Ann. Neurol. 2007; 61: 162-174
- Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway.Hum. Mol. Genet. 2015; 24: 4516-4529
- Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia.Brain. 2011; 134: 1387-1399
- Novel splice variants increase molecular diversity of aprataxin, the gene responsible for early-onset ataxia with ocular motor apraxia and hypoalbuminemia.Neurosci. Lett. 2004; 366: 120-125
- Type 1 ataxia with oculomotor apraxia with aprataxin gene mutations in two American children.J. Child Neurol. 2005; 20: 619-620
- Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients.Neurogenetics. 2011; 12: 193-201
- Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies.Brain. 2003; 126: 2761-2772
- Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations.Neurology. 2002; 59: 590-595
- Short half-lives of ataxia-associated aprataxin proteins in neuronal cells.Neurosci. Lett. 2007; 419: 184-187
- The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates.Nature. 2006; 443: 713-716
Article info
Publication history
Published online: April 29, 2017
Accepted:
April 28,
2017
Received in revised form:
April 14,
2017
Received:
December 3,
2016
Identification
Copyright
© 2017 Elsevier B.V. All rights reserved.
