Article

A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1

Centre National de Génotypage, Évry-Petit-Bourg, Île-de-France, France
Annals of Neurology (Impact Factor: 11.91). 12/2002; 52(5):666-70. DOI: 10.1002/ana.10344
Source: PubMed

ABSTRACT We investigated a French family with a new type of autosomal dominant spinocerebellar ataxia that was excluded from all previously identified genes and loci. The patients exhibited a slowly progressive gait and limb ataxia variably associated with akinesia, rigidity, tremor, and hyporeflexia. A mild cognitive impairment also was observed in some cases. We performed a genomewide search and found significant evidence for linkage to chromosome 7p21.3-p15.1. Analysis of key recombinants and haplotype reconstruction traced this novel spinocerebellar ataxia locus to a 24cM interval flanked by D7S2464 and D7S516.

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Available from: Francis Vasseur, Dec 09, 2014
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    • "In previous work, we characterized a 24-member French family pedigree, 11 members of which were affected by a new form of SCA (Devos et al., 2001). The disease locus was initially mapped to chromosome 7 and designated as SCA21 (Vuillaume et al., 2002). After examination of 12 additional family members, we reconsidered our linkage analysis. "
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    ABSTRACT: Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.
    Brain 07/2014; 137. DOI:10.1093/brain/awu202 · 10.23 Impact Factor
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    • "Autosomal dominant cerebellar ataxia (ADCA)-I, a more heterogeneous group that includes SCA1, SCA2, SCA3, SCA4, SCA8, SCA12, SCA13, SCA18-25, SCA27-29, and dentatorubral-pallidoluysian atrophy (DRPLA), presents with pyramidal features, extrapyramidal signs, and amyotrophy [Orr et al., 1993; Imbert et al., 1996; Pulst et al., 1996; Kawaguchi et al., 1994; Flanigan et al., 1996; Koob et al., 1999; Holmes et al., 1999; Waters et al., 2006; Devos et al., 2001; Verbeek et al., 2004; Knight et al., 2004; Vuillaume et al., 2002; Chung et al., 2003; Schelhaas et al., 2004; Swartz et al., 2002; Stevanin et al., 2005; Yu et al., 2005; van Swieten et al., 2003; Cagnoli et al., 2006; Koide et al., 1994]. Additionally, pigmentary retinal degeneration and seizures are observed in ADCA-II (SCA7) and ADCA-IV (SCA10 and SCA17), respectively [David et al., 1997; Matsuura et al., 2000; Nakamura et al., 2001]. "
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    ABSTRACT: Repeat expansion has been implicated in 10 out of 17 candidate genes identified for autosomal dominant cerebellar ataxias (ADCAs)-commonly referred as spinocerebellar ataxias (SCAs). Though genetically distinct, the SCAs share a large number of features that confound their clinical classification. In addition, there is a difference in the prevalence and phenotypic expression of ataxias between different ethnic groups. We have created a new SCA-locus-specific variation database (LSVD) that aims to catalog and integrate information on SCAs associated with trinucleotide repeat expansion (SCA1, SCA 2, SCA 3, SCA 6, SCA 7, SCA 8, SCA 12, SCA 17, Friedreich's ataxia [FRDA], and dentatorubral-pallidoluysian atrophy [DRPLA]) from all over the world. The database has been developed using the Leiden Open (source) Variation Database (LOVD) software (Leiden University Medical Center, Leiden, the Netherlands). The database houses detailed information on clinical features, such as age and symptom at onset, mode of inheritance, and genotype information, pertaining to the SCA patients from more than 400 families across India. All the compiled genotype data conforms to the HGVS Nomenclature guidelines. This would be a very useful starting point for understanding the molecular correlates of phenotypes in ataxia-a multilocus disease in which related molecular mechanisms converge to overlapping phenotypes.
    Human Mutation 07/2009; 30(7):1037-42. DOI:10.1002/humu.21006 · 5.05 Impact Factor
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    • "PRKCG PRKCG MM Chen et al. (2003a) SCA15 3p24.2-pter U U U Gardner et al. (2005) SCA16 8q23-q24.1 U U U Miyoshi et al. (2001) SCA17 6q27 TBP TBP CAG repeat Nakamura et al. (2001) SCA18 7q31-q32 U U U Devos et al. (2001) SCA19* 1p21-q21 U U U Verbeek et al. (2002) SCA20 11 U U U Knight et al. (2004) SCA21 7p21.3-p15.1 U U U Vuillaume et al. (2002) SCA22* 1p21-q23 U U U Chung et al. (2003) SCA23 20p13-p12.2 U U U Verbeek et al. (2004) SCA24 1p36 U U U Swartz et al. (2002) SCA25 2p21-p15 U U U Stevanin et al. (2005) SCA26 19p13.3 "
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    ABSTRACT: The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its afferent and efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly understood. Compelling evidence points to major aetiological roles for interference with transcriptional regulation, protein aggregation and clearance, the ubiquitin-proteasome system and alterations of calcium homeostasis in the neuronal loss observed during the neurodegenerative process. But novel molecular routes that might be disrupted during disease progression are also being identified. These pathways could act independently or, more likely, interact and enhance each other, triggering the accumulation of cellular damage that eventually leads to dysfunction and, ultimately, the demise of neurons through a series of multiple events. This suggests that simultaneous targeting of several pathways might be therapeutically necessary to prevent neurodegeneration and preserve neuronal function. Understanding how dysregulation of these pathways mediates disease progression is leading to the establishment of effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the current therapeutic strategies.
    Brain 07/2006; 129(Pt 6):1357-70. DOI:10.1093/brain/awl081 · 10.23 Impact Factor
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