Molecular genetics of spinocerebellar ataxia type 8 (SCA8)

Mosemiller, Anne K; Dalton, Joline; Day, John W.; Ranum, Laura P.W.

doi:10.1159/000072852

Cited by 29 publications

(30 citation statements)

References 56 publications

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“…The expansion, which contained 80 CTGNCAG repeats, preceded by 11 CTANTAG repeats, maps to chromosome 13q21. We subsequently found this expansion in a seven-generation ataxia kindred (the MN-A family), and by studying 92 members of that family were able to genetically confirm the relationship of the mutation to the clinical disease with a LOD score of 6.8 at h50.00 (2,4,5). According to our initial sequence analysis of the SCA8 CTGNCAG repeat region, there were no likely open reading frames identified in the CTG or CAG direction, but we initially showed that the CTG direction was transcribed, and that transcripts expressed and containing the CUG expansion are primarily expressed in the central nervous system and cerebellum (4).…”

Section: Identification Of the Sca8 Ctgncag Repeat Expansion Mutationmentioning

confidence: 98%

“…This method, called repeat analysis, pooled isolation and detection (RAPID) cloning (2), used the repeat expansion detection (RED) assay (3), and several cloning and enrichment steps to identify CAGNCTG expansions and their corresponding flanking sequence (2,4,5). This method can be used to isolate candidate genes without requiring linkage studies and the identification of large families and provides a strategy for identifying genetic mutations causing diseases with reduced penetrance.…”

Section: Identification Of the Sca8 Ctgncag Repeat Expansion Mutationmentioning

confidence: 99%

“…Clinical evaluations of over 200 patients from 25 separate families indicate that SCA8 presents as a slowly progressive ataxia that largely spares brainstem and cerebral function (4)(5)(6)(7)(8)(9)(10)(11). In the MN-A family, disease onset ranges from 13-60 years of age with the most frequently reported symptom being gait incoordination.…”

Section: Clinical Features Of Sca8mentioning

confidence: 99%

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Bidirectional expression of the SCA8 expansion mutation: One mutation, two genes

2008

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Spinocerebellar ataxia type 8 (SCA8) is a dominantly inherited, slowly progressive neurodegenerative disorder caused by a CTG.CAG repeat expansion located on chromosome 13q21. The expansion mutation was isolated directly from the DNA of a single patient using RAPID cloning and subsequently shown to co-segregate with disease in additional ataxia families including a seven-generation kindred (the MN-A family). The size-dependent penetrance of the repeat found in the large MN-A kindred makes it appear as though some parts of the family have a dominant disorder while other parts of this same family have recessive or sporadic forms of ataxia. While the linkage and size-dependent penetrance of the SCA8 CTG.CAG expansion in the MN-A family argue that the SCA8 expansion causes ataxia, the reduced penetrance in other SCA8 families and the discovery of expansions in the general population have led to a controversy surrounding whether or not the SCA8 expansion is pathogenic. A recently reported mouse model in which SCA8 BAC-expansion but not BAC-control lines develop a progressive neurological phenotype now demonstrates the pathogenicity of the (CTG.CAG)(n) expansion. These mice show a loss of cerebellar GABAergic inhibition and, similar to human patients, have 1C2-positive intranuclear inclusions in Purkinje cells and other neurons. Additional studies demonstrate that the SCA8 expansion is expressed in both directions (CUG and CAG) and that a novel gene expressed in the CAG direction encodes a pure polyglutamine expansion protein (ataxin 8, ATXN8). Moreover, the expression of non-coding (CUG)(n) expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggest SCA8 pathogenesis may involve toxic gain-of-function mechanisms at both the protein and RNA levels. Our data, combined with the recently reported antisense transcripts spanning the DM1 repeat expansion in the CAG direction and the growing number of reports of antisense transcripts expressed throughout the mammalian genome, raises the possibility that bidirectional expression across pathogenic microsatellite expansions may occur in other expansion disorders, and that potential pathogenic effects of mutations expressed from both strands should be considered.

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Section: Identification Of the Sca8 Ctgncag Repeat Expansion Mutationmentioning

confidence: 98%

Section: Identification Of the Sca8 Ctgncag Repeat Expansion Mutationmentioning

confidence: 99%

Section: Clinical Features Of Sca8mentioning

confidence: 99%

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Bidirectional expression of the SCA8 expansion mutation: One mutation, two genes

2008

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“…Recently, mismatches in triplet repeat structures have been hypothesized to be the origin of genetic instabilities that lead to DNA mutations [20][21][22][23][24][25]. During DNA replication, repair and recombination, slippage in single strands of CAG and CTG repeats can occur, forming slipped strand structures with AAEA and TAET mismatches, respectively [26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Proton chemical shift prediction of A·A mismatches in B-DNA duplexes

Lam

Lai

Man

2007

Journal of Magnetic Resonance

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A proton chemical shift prediction method has been developed for double helical DNAs containing A.A mismatches. This method makes use of the chemical shift prediction scheme for normal B-DNA duplexes developed by Altona and co-workers and a set of A.A mismatch triplet chemical shift values and corrections factors extracted from reference sequences. The triplet values are used for predicting chemical shifts of A.A mismatches whereas the normal B-DNA chemical shifts and correction factors are used for the flanking residues of A.A mismatches. Both 5'- and 3'-correction factors have been determined from the chemical shift differences upon replacing the A.A mismatch in a duplex with an A.T base pair. Based on 560 sets of predicted and experimental chemical shifts, the overall prediction accuracy for various types of protons has been determined to be 0.07 ppm with an excellent correlation coefficient of 0.9996.

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“…Progression is slow, with ambulatory aids often not being required during the first 20 years of illness. Symptom severity correlates with repeat length and age (Mosemiller et al, 2003;Ikeda et al, 2004). One case with congenital onset presented with severe cerebellar symptoms in the first year, myoclonic epilepsy at 3 years, and mental retardation.…”

Section: Clinical Featuresmentioning

confidence: 99%

Spinocerebellar degenerations

Perlman

2011

Handbook of Clinical Neurology

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Molecular genetics of spinocerebellar ataxia type 8 (SCA8)

Cited by 29 publications

References 56 publications

Bidirectional expression of the SCA8 expansion mutation: One mutation, two genes

Bidirectional expression of the SCA8 expansion mutation: One mutation, two genes

Proton chemical shift prediction of A·A mismatches in B-DNA duplexes

Spinocerebellar degenerations

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