Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy

Igarashi, Shuichi; Tanno, Y; Onodera, Osamu; Yamazaki, Miwa; Sato, Kimiyasu; Ishikawa, Akari; Miyatani, Nobuyuki; Nagashima, Masaharu; Ishikawa, Yoshihiro; Sahashi, Kentaro; Ibi, Takayuki; Miyatake, Tadashi; Tsuji, Shoji

doi:10.1212/wnl.42.12.2300

Cited by 168 publications

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“…In two studies 10,11 correlation between the repeat length and more severe symptoms and earlier onset of SBMA is reported, but in two other studies 20,21 no correlation was found. In our study, weak negative correlation was found between the CAG repeat length and the age of onset in the 95 SBMA patients with defined ages at onset, but when the patients from different countries were examined separately, the correlation was detected only in the Japanese patients.…”

Section: Discussionmentioning

confidence: 95%

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Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world

et al. 2001

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SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.

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Section: Discussionmentioning

confidence: 95%

“…The longer the repeat, the more severe the symptoms are and the earlier the onset of the disease. 10,11 Most Finnish SBMA patients come from the district of Vaasa in Western Finland. 3 We have shown that all the Finnish families share identical alleles for at least five nearby markers around the AR gene.…”

Section: Introductionmentioning

confidence: 99%

Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world

et al. 2001

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“…In SBMA, a polymorphic CAG repeat with 14 -32 CAGs expands to 40 -62 CAGs in the first exon of the androgen receptor (AR) gene (La Spada et al, 1991;Tanaka et al, 1996). CAG repeat size is inversely correlated with the age at onset and positively correlated with disease severity in SBMA (Doyu et al, 1992;Igarashi et al, 1992;La Spada et al, 1992). The histopathologic hallmarks of SBMA are lower motor neuronal loss (Sobue et al, 1989), diffuse nuclear accumulation, and nuclear inclusions (NIs) of expanded polyQ mutant AR in the residual motor neurons in brainstem and spinal cord as well as in some other visceral organs (Li et al, 1998a,b;.…”

Section: Introductionmentioning

confidence: 99%

CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model

Adachi¹,

Waza²,

Tokui³

et al. 2007

J. Neurosci.

133

143

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Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor (AR). The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of the mutant AR in the residual motor neurons and certain visceral organs. Many components of the ubiquitin-proteasome and molecular chaperones are also sequestered in the inclusions, suggesting that they may be actively engaged in an attempt to degrade or refold the mutant AR. C terminus of Hsc70 (heat shock cognate protein 70)-interacting protein (CHIP), a U-box type E3 ubiquitin ligase, has been shown to interact with heat shock protein 90 (Hsp90) or Hsp70 and ubiquitylates unfolded proteins trapped by molecular chaperones and degrades them. Here, we demonstrate that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wild type. High expression of CHIP in an SBMA transgenic mouse model also ameliorated motor symptoms and inhibited neuronal nuclear accumulation of the mutant AR. When CHIP was overexpressed in transgenic SBMA mice, mutant AR was also preferentially degraded over wild-type AR. These findings suggest that CHIP overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR via enhanced mutant AR degradation. Thus, CHIP overexpression would provide a potential therapeutic avenue for SBMA.

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“…In SBMA patients, a normally polymorphic CAG repeat (10 -36 CAGs) expands to 38 -66 CAGs. The number of CAGs is inversely correlated with the age of onset of the disease (2)(3)(4). To date, seven other CAG repeat diseases have been identified, including Huntington's disease (5), dentatorubralpallidoluysian atrophy (6,7), and five spinocerebellar ataxias: 1, 2, 3, 6, and 7) (8 -14).…”

mentioning

confidence: 99%

Chaperones Hsp70 and Hsp40 Suppress Aggregate Formation and Apoptosis in Cultured Neuronal Cells Expressing Truncated Androgen Receptor Protein with Expanded Polyglutamine Tract

Kobayashi¹,

Kume²,

Li³

et al. 2000

Journal of Biological Chemistry

302

165

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Spinal and bulbar muscular atrophy (SBMA) is one of a group of human inherited neurodegenerative diseases caused by polyglutamine expansion. We have previously demonstrated that the SBMA gene product, the androgen receptor protein, is toxic and aggregates when truncated. Heat shock proteins function as molecular chaperones, which recognize and renaturate misfolded protein (aggregate). We thus assessed the effect of a variety of chaperones in a cultured neuronal cell model of SBMA. Overexpression of chaperones reduces aggregate formation and suppresses apoptosis in a cultured neuronal cell model of SBMA to differing degrees depending on the chaperones and their combinations. Combination of Hsp70 and Hsp40 was the most effective among the chaperones in reducing aggregate formation and providing cellular protection, reflecting that Hsp70 and Hsp40 act together in chaperoning mutant and disabled proteins. Although Hdj2/Hsdj chaperone has been previously reported to suppress expanded polyglutamine tract-formed aggregate, Hsdj/Hdj2 showed little effect in our system. These findings indicate that chaperones may be one of the key factors in the developing of CAG repeat disease and suggested that increasing expression level or enhancing the function of chaperones will provide an avenue for the treatment of CAG repeat disease.

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Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy

Cited by 168 publications

References 0 publications

Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world

Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world

CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model

Chaperones Hsp70 and Hsp40 Suppress Aggregate Formation and Apoptosis in Cultured Neuronal Cells Expressing Truncated Androgen Receptor Protein with Expanded Polyglutamine Tract

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