Disease relevance of ATN1

• Dentatorubral-pallidoluysian atrophy (DRPLA) is one of the hereditary neurodegenerative disorders caused by expansion of CAG/glutamine repeats [1].
• Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), also shows CAG/CTG repeat expansions [2].
• The aim of the study was to evaluate the occurrence of spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA) in Finland, and to investigate the role of predisposing normal alleles in a genetically homogenous population [3].
• While previous data suggest that meiotic drive may be a feature of certain human diseases, including the trinucleotide diseases MJD, myotonic dystrophy, and dentatorubral-pallidoluysian atrophy, these data are compatible with meiotic drive also occurring among non-disease associated CAG sizes [4].
• To date, nine polyglutamine disorders have been characterised, including Huntington's disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxias 1, 2, 3, 6, 7 and 17 (SCAs) [5].

Psychiatry related information on ATN1

• Late onset DRPLA may thus be misdiagnosed to other disease categories, when dementia was not apparent at the time of onset [6].
• We conclude that variation at the DRPLA locus is unlikely to be associated with periodic catatonia [7].
• Early-onset childhood dentatorubral-pallidoluysian atrophy involved mental retardation, whereas myoclonic epilepsy was the predominant complaint in later-onset childhood version of the disease [8].

High impact information on ATN1

• Dentatorubral-pallidoluysian atrophy is a progressive neurodegenerative disease caused by the expansion of a polyglutamine repeats within the Atrophin-1 protein [9].
• We found that truncated DRPLA proteins containing an expanded polyglutamine stretch form filamentous peri- and intranuclear aggregates and undergo apoptosis [10].
• Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch [10].
• To elucidate the molecular mechanisms whereby expanded polyglutamine stretches elicit a gain of toxic function, we expressed full-length and truncated DRPLA (dentatorubral-pallidoluysian atrophy) cDNAs with or without expanded CAG repeats in COS-7 cells [10].
• Dentatorubral-pallidoluysian atrophy (DRPLA) is associated with the expansion of an unstable CAG repeat [11].

Chemical compound and disease context of ATN1

• Furthermore, the immunoliposomes could inhibit the growth of DXR-insensitive stomach cancer cells (B37) in an in vivo model [12].

Biological context of ATN1

• However, the segregation ratio of single sperm with an expanded allele to ones with a normal allele is not statistically different ( P = 0.161) from the expected 1:1 segregation ratio, and thus segregation distortion of expanded alleles in meiosis in male patients with DRPLA was not demonstrated [13].
• The gene isolated, designated RERE, has an open reading frame of 1566 amino acids, of which the C-terminal portion has 67% homology to DRPLA, whereas the N-terminal portion is distinctive [1].
• Protein binding of a DRPLA family through arginine-glutamic acid dipeptide repeats is enhanced by extended polyglutamine [1].
• The identification of IRSp53 and other proteins detected by the yeast hybrid system predicts that DRPLA functions in a signal transduction pathway coupled with insulin/IGF-1 [14].
• Dentatorubral-pallidoluysian atrophy (DRPLA) is known to show the most prominent genetic anticipation among CAG repeat diseases [13].

Anatomical context of ATN1

• The discrepancy in the expanded CAG repeat length between cerebellar cortex and other tissues was most prominent in DRPLA, and especially in cases of adult-onset DRPLA [15].
• In addition, all cases of DRPLA showed a reduction of immunoreactivity for EAAT1 in the dentate nucleus [16].
• The lesion of Purkinje cells and their processes in the molecular layer associated with altered glutamate transport may be important in DRPLA, while the significance of the abnormalities observed in some MJD cases, which might be related to apoptotic mechanism, remains unclear [16].
• The expanded CAG repeats of the mRNA were shorter in the cerebellum than in other regions of the central nervous system in DRPLA and MJD, but not in SBMA, and were longer in the liver and colon in MJD [17].
• In transient cell transfection experiments using a neuroblastoma cell line, full-length atrophin-1 with 26 (normal) or 65 (expanded) glutamines localized to both nucleus and cytoplasm, with no significant difference in toxicity between the normal and mutant proteins [18].

Associations of ATN1 with chemical compounds

• Dentatorubral-pallidoluysian atrophy protein interacts through a proline-rich region near polyglutamine with the SH3 domain of an insulin receptor tyrosine kinase substrate [14].
• Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neuro degrees enerative disorder associated with CAG/glutamine repeat expansion [14].
• Four target genes, which show homology to ATN1-like protein kinase, NAC transcription factors and a cytokinin receptor, have been validated by miRNA-mediated mRNA cleavage [19].
• The CAG repeat, which is expanded in DRPLA, is located 1,462 bp downstream from the putative methionine initiation codon and encodes a poly-glutamine tract [20].
• Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-Jun NH2-terminal kinase [21].

Physical interactions of ATN1

• Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH [22].

Enzymatic interactions of ATN1

• Selective colocalization of transglutaminase-like activity in ubiquitinated intranuclear inclusions of hereditary dentatorubral-pallidoluysian atrophy [23].

Co-localisations of ATN1

• Moreover, when RERE is overexpressed, the distribution of endogenous DRPLA protein alters from the diffused to the speckled pattern in the nucleus so as to co-localize with RERE [1].

Regulatory relationships of ATN1

• Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy. Influence of CAG repeat size on MRI findings [24].

Other interactions of ATN1

• More RERE protein is recruited into nuclear aggregates of the DRPLA protein with extended polyglutamine than into those of pure polyglutamine [1].
• Binding of the DRPLA protein to IRSp53 was ascertained by co-immunoprecipitation with antibodies and also by co-localization in perinuclear oval dots in cells expressing engineered constructs [14].
• A family with Machado-Joseph disease, previously diagnosed as dentatorubral-pallidoluysian atrophy [25].
• The variance of the change in CAG repeat size was significantly different between the two DRPLA patients (F-test, P < 0.0001) [13].
• MATERIAL AND METHODS: Mutation analyses for SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA and frataxin genes were performed for 251 unrelated Finnish patients who presented with progressive ataxia disorder [3].

Analytical, diagnostic and therapeutic context of ATN1

• Molecular cloning of a full-length cDNA for dentatorubral-pallidoluysian atrophy and regional expressions of the expanded alleles in the CNS [20].
• Epidemiological studies have demonstrated an increased prevalence of DRPLA in Japan, although several DRPLA kindreds of non-Japanese ancestry have been identified [26].
• The mutation analysis by PCR excluded diagnoses of SCA-1, -2, -3, -6, -7, -8, and -12 and DRPLA [27].
• Reverse transcriptase-polymerase chain reaction analysis showed DRPLA gene expression in corneal endothelial cells [28].
• Assignment of the dentatorubral and pallidoluysian atrophy (DRPLA) gene to 12p 13.31 by fluorescence in situ hybridization [29].

References