Aprataxin gene mutations in Tunisian families

Amouri, Rim; Moreira, Maria-Céu; Zouari, M.; Euch, G. El; Barhoumi, C.; Kéfi, M.; Belal, Samir; Kœnig, M.; Hentati, Fayçal

doi:10.1212/01.wnl.0000137044.06573.46

Cited by 43 publications

(30 citation statements)

References 8 publications

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“…The deletion mutant, 840delT (2), introduces a frameshift immediately after the W279R missense codon (30), which is also the site of truncation in W279X, the Portuguese founder allele (3,29,30) that has been more recently identified in an American family with coenzyme Q deficiency and cerebellar ataxia (4). The Tunisian splice site alteration, IVS7 ϩ 1, is also expected to truncate the protein NH 2 -terminal to the zinc finger (31). Thus, the 689insT allele is a Hint domain truncation, while the 840delT, W279X, and IVS7 ϩ 1 alleles are zinc finger domain truncation mutants.…”

Section: Resultsmentioning

confidence: 99%

Disease-associated Mutations Inactivate AMP-Lysine Hydrolase Activity of Aprataxin

Seidle

Bieganowski

Brenner

2005

Journal of Biological Chemistry

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Ataxia-oculomotor apraxia syndrome 1 is an early onset cerebellar ataxia that results from loss of function mutations in the APTX gene, encoding Aprataxin, which contains three conserved domains. The forkhead-associated domain of Aprataxin mediates protein-protein interactions with molecules that respond to DNA damage, but the cellular phenotype of the disease does not appear to be consistent with a major loss in DNA damage responses. Disease-associated mutations in Aprataxin target a histidine triad domain that is similar to Hint, a universally conserved AMP-lysine hydrolase, or truncate the protein NH 2 -terminal to a zinc finger. With novel fluorigenic substrates, we demonstrate that Aprataxin possesses an active-site-dependent AMP-lysine and GMP-lysine hydrolase activity that depends additionally on the zinc finger for protein stability and on the forkhead associated domain for enzymatic activity. Alleles carrying any of eight recessive mutations associated with ataxia and oculomotor apraxia encode proteins with huge losses in protein stability and enzymatic activity, consistent with a null phenotype. The mild presentation allele, APTX-K197Q, associated with ataxia but not oculomotor apraxia, encodes a protein with a mild defect in stability and activity, while enzyme encoded by the atypical presentation allele, APTX-R199H, retained substantial function, consistent with altered and not loss of activity. The data suggest that the essential function of Aprataxin is reversal of nucleotidylylated protein modifications, that all three domains contribute to formation of a stable enzyme, and that the in vitro behavior of cloned APTX alleles can score disease-associated mutations.

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Section: Resultsmentioning

confidence: 99%

Disease-associated Mutations Inactivate AMP-Lysine Hydrolase Activity of Aprataxin

Seidle

Bieganowski

Brenner

2005

Journal of Biological Chemistry

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“…Deletion of the APTX gene has been previously reported in a single family with two affected members; however, these patients were described as having no cognitive deficit, and the neurological symptoms were not assessed as being more severe compared with the classical phenotype 3. Although ataxia is the presenting symptom in the vast majority of reported cases, our patient presented with behavioural changes (withdrawal from previously normal social contact) and difficulties with language acquisition.…”

Section: Discussionmentioning

confidence: 67%

Complete deletion of the aprataxin gene: ataxia with oculomotor apraxia type 1 with severe phenotype and cognitive deficit

Yoon

Westmacott²,

MacMillan³

et al. 2009

Case Reports

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Ataxia with oculomotor apraxia type 1 (AOA1) is a recently described autosomal-recessive neurodegenerative condition of childhood onset. It is caused by mutations in the APTX gene, which encodes the protein aprataxin. Clinical features include gait and limb ataxia, dysarthria, oculomotor apraxia, mild peripheral neuropathy and progression of neurological deficits.1 Some patients manifest parkinsonian symptoms or mental retardation, although the latter has been reported predominantly in Japanese patients.2 We report a patient with homozygous deletion of APTX, who presented with behavioural changes (social withdrawal), and subsequent rapid progression of neurological symptoms associated with severe cognitive decline. We suggest that complete deletion of APTX is associated with a more severe phenotype than that associated with point mutations.

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“…The proband showed shortrapid movements in her fingers, but was able to control them, challenging their choreic origin. Third, mental retardation or cognitive impairment are common in Japanese and French patients [2,3] manifesting a dysexecutive syndrome related to dysfunction of the front-cerebellar pathways [3]; the proband did not disclosed mental retardation or cognitive impairment similarly to Portuguese and Tunisian patients [12,13]. Fourth, some authors consider the presence of Babinski sign a distinctive trait of FRDA as to AOA [3].…”

Section: Discussionmentioning

confidence: 99%

A novel mutation of aprataxin associated with ataxia ocular apraxia type 1: Phenotypical and genotypical characterization

Ferrarini

Squintani

Cavallaro

et al. 2007

Journal of the Neurological Sciences

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Aprataxin gene mutations in Tunisian families

Cited by 43 publications

References 8 publications

Disease-associated Mutations Inactivate AMP-Lysine Hydrolase Activity of Aprataxin

Disease-associated Mutations Inactivate AMP-Lysine Hydrolase Activity of Aprataxin

Complete deletion of the aprataxin gene: ataxia with oculomotor apraxia type 1 with severe phenotype and cognitive deficit

A novel mutation of aprataxin associated with ataxia ocular apraxia type 1: Phenotypical and genotypical characterization

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