Phenotypic variability of
            <i>aprataxin</i>
            gene mutations

Tranchant, Christine; Fleury, Marie-Céline; Moreira, Maria-Céu; Kœnig, M.; Warter, J

doi:10.1212/01.wnl.0000048562.88536.a4

Cited by 73 publications

(64 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…AOA1 should therefore be considered as a possible diagnosis in all patients with early-onset cerebellar ataxia with or without familial histories, after exclusion of Friedreich's ataxia. The most frequent AOA1 phenotype associates cerebellar ataxia with cerebellar atrophy visualized by MRI, chorea, axonal sensorimotor neuropathy and deep sensory loss as previously described (Shimazaki et al, 2002;Tranchant et al, 2003). OMA, which is the hallmark of the disease, is present in most (86%), but not all patients.…”

Section: Discussionmentioning

confidence: 73%

Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Ber¹

2003

Brain

213

View full text Add to dashboard Cite

SummaryAtaxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identi®ed recently. We studied a large series of 158 families with non-Friedreich progressive ARCA. We identi®ed 14 patients (nine families) with ®ve different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 T 4.8 years (range 2±18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with`slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's disease.

show abstract

Section: Discussionmentioning

confidence: 73%

Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Ber¹

2003

Brain

213

View full text Add to dashboard Cite

show abstract

“…This evidence stems from its interaction with a number of proteins involved in DNA break repair, including poly(ADP- FIGURE 7. A, the effect of the 21-bp duplex DNA on the catalytic activity of Aprataxin (1 mM) using Ap 4 A as a substrate. The velocity of the reaction is expressed as a percent of the control reaction, that has no DNA and is plotted against increasing DNA concentration in the presence of 500 M Ap 4 A.…”

Section: Discussionmentioning

confidence: 99%

“…Two different size transcripts were identified for Aprataxin by Northern blot analysis and sequencing and were predicted to encode short (19 kDa) and long (39 kDa) forms of the protein. A series of mutations has been described in APTX, primarily localizing to the histidine triad (HIT) domain centrally located in the molecule (1,4). Aprataxin also contains an N-terminal Forkhead-associated (FHA) domain that binds phosphoproteins and a C-terminal putative zinc finger DNA binding domain (2,3,5,6).…”

mentioning

confidence: 99%

Aprataxin Forms a Discrete Branch in the HIT (Histidine Triad) Superfamily of Proteins with Both DNA/RNA Binding and Nucleotide Hydrolase Activities

Kijas

Harris

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset autosomal recessive spinocerebellar ataxia with a defect in the protein Aprataxin, implicated in the response of cells to DNA damage. We describe here the expression of a recombinant form of Aprataxin and show that it has dual DNA binding and nucleotide hydrolase activities. This protein binds to double-stranded DNA with high affinity but is also capable of binding double-stranded RNA and single-strand DNA, with increased affinity for hairpin structures. No increased binding was observed with a variety of DNA structures mimicking intermediates in DNA repair. The DNA binding observed here was not dependent on zinc, and the addition of exogenous zinc abolished DNA binding. We also demonstrate that Aprataxin hydrolyzes with similar efficiency the model histidine triad nucleotide-binding protein substrate, AMPNH 2 , and the Fragile histidine triad protein substrate, Ap 4 A. These activities were significantly reduced in the presence of duplex DNA and to a lesser extent in the presence of single-strand DNA, and removal of the N-terminal Forkhead associated domain did not alter activity. Finally, comparison of sequence relationships between the histidine triad superfamily members shows that Aprataxin forms a distinct branch in this superfamily. In addition to its capacity for nucleotide binding and hydrolysis, the observation that it also binds DNA and RNA adds a new dimension to this superfamily of proteins and provides further support for a role for Aprataxin in the cellular response to DNA damage.

show abstract

“…Aprataxin is a member of the histidine triad (HIT) superfamily of nucleotide hydrolases and transferases, and it removes 5′-AMP groups that arise from aborted DNA ligation reactions (3)(4)(5)(6). The clinical symptoms of AOA1 include global cerebellar atrophy characterized by loss of Purkinje cells, ocular motor apraxia, and motor and sensory neuropathy (7)(8)(9)(10)(11)(12)(13). The pathophysiology of AOA1 overlaps with both Friedreich's ataxia (FA) and Ataxia-Telangiectasia (A-T), rare disorders that present with similar neurological symptoms but different underlying genetic mutations (14).…”

mentioning

confidence: 99%

Aprataxin localizes to mitochondria and preserves mitochondrial function

Sýkora

Croteau

Bohr

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Ataxia with oculomotor apraxia 1 is caused by mutation in the APTX gene, which encodes the DNA strand-break repair protein aprataxin. Aprataxin exhibits homology to the histidine triad superfamily of nucleotide hydrolases and transferases and removes 5′-adenylate groups from DNA that arise from aborted ligation reactions. We report herein that aprataxin localizes to mitochondria in human cells and we identify an N-terminal amino acid sequence that targets certain isoforms of the protein to this intracellular compartment. We also show that transcripts encoding this unique N-terminal stretch are expressed in the human brain, with highest production in the cerebellum. Depletion of aprataxin in human SH-SY5Y neuroblastoma cells and primary skeletal muscle myoblasts results in mitochondrial dysfunction, which is revealed by reduced citrate synthase activity and mtDNA copy number. Moreover, mtDNA, not nuclear DNA, was found to have higher levels of background DNA damage on aprataxin knockdown, suggesting a direct role for the enzyme in mtDNA processing.

show abstract

Phenotypic variability of aprataxin gene mutations

Cited by 73 publications

References 7 publications

Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Aprataxin Forms a Discrete Branch in the HIT (Histidine Triad) Superfamily of Proteins with Both DNA/RNA Binding and Nucleotide Hydrolase Activities

Aprataxin localizes to mitochondria and preserves mitochondrial function

Contact Info

Product

Resources

About