A Fine Integrated Map of the SPG4 Locus Excludes an Expanded CAG Repeat in Chromosome 2p-Linked Autosomal Dominant Spastic Paraplegia

Hazan, Jamilé; Davoine, Claire-Sophie; Mavel, Delphine; Fonknechten, Nùria; Paternotte, Caroline; Fizames, Cécile; Cruaud, Corinne; Samson, Delphine; Muselet, Delphine; Vega-Czarny, Nathalie; Brice, Alexis; Gyapay, Gábor; Heilig, Roland; Fontaine, Bertrand; Weissenbach, Jean

doi:10.1006/geno.1999.5932

Cited by 12 publications

(6 citation statements)

References 47 publications

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“…Clinical anticipation has been reported for 14q [Gispert et al, 1995] and SPG4 kindreds by Nielsen et al [1997], who reported CAG repeat expansion in six Danish families. However, clinical anticipation is apparently an infrequent finding [Fink et al, 1996] and recent studies excluded expanded CAG repeat in a new series of SPG4 families [Hazan et al, 1999b]. In the present family comparison between subject II‐2 and her offspring as well as individuals III‐3 and IV‐2 does not suggest clinical anticipation in accordance with Hedera's family.…”

Section: Discussionsupporting

confidence: 53%

Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: Analysis of muscle beta 1 syntrophin

et al. 2000

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The autosomal dominant hereditary spastic paraplegias (AD-HSP) are a heterogeneous group of degenerative disorders of the central motor system, characterized by progressive spasticity of the lower limbs. Five loci for pure AD-HSP have been identified to date: SPG3 at 14q, SPG4 at 2p, SPG6 at 15q, SPG8 at 8q, and more recently SPG10 at 12q. We have analyzed a Brazilian family with 16 affected individuals by pure AD-HSP who developed progressive gait disturbance with onset at age 18-26 years. Linkage analysis performed with 13 relatives (6 affected and 7 normal) excluded SPG3, SPG4, and SPG6 as candidate regions. However, positive LOD scores were obtained with markers flanking the candidate region for the SPG8 locus [maximum two point Lod score (Zmax) = 3.3 at theta = 0 for D8S1804]. In this region lies the syntrophin beta 1 gene (SNT2B1), a widely expressed dystrophin-associated protein and therefore a good positional and functional candidate for this disease. Immunohistochemical and Western Blot (WB) studies showed that the distribution, expression, and apparent molecular weight of the beta 1 syntrophin protein were comparable to those of normal control individuals. Therefore, it is unlikely that defects in this protein are related to SPG8, at least in the present family.

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Section: Discussionsupporting

confidence: 53%

Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: Analysis of muscle beta 1 syntrophin

et al. 2000

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“…The haplotypes observed with these eight markers are shown in fig 1. The order of the markers is consistent with the physical map of the region. 22 Recombination events were observed for III.44, IV.4, IV.6, and IV.8.…”

Section: Resultsmentioning

confidence: 97%

Autosomal dominant (AD) pure spastic paraplegia (HSP) linked to locus SPG4 affects almost exclusively males in a large pedigree

Starling

2002

Journal of Medical Genetics

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“…If these conjectures are correct, this would represent an unusual explanation of the dominant and recessive effects of different mutations in the same gene. This hypothesis was recently also postulated to explain dominant and recessive mutations in the connexin31 gene27 (a gene causing non-syndromic hearing loss), although as both dominant and recessive mutations in this gene were missense it was not clear whether the dominant mutations caused the disease through haploinsufficiency or dominant negative effects. If the latter is the case then the recessive mutations in this gene are likely to be null mutations.…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis

Lindsey

Lusher²,

McDermott³

et al. 2000

Journal of Medical Genetics

123

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Background-Hereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22. Objectives-To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22. Methods-DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically. Results-Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which aVect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation. Conclusions-Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients. (J Med Genet 2000;37:759-765)

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A Fine Integrated Map of the SPG4 Locus Excludes an Expanded CAG Repeat in Chromosome 2p-Linked Autosomal Dominant Spastic Paraplegia

Cited by 12 publications

References 47 publications

Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: Analysis of muscle beta 1 syntrophin

Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: Analysis of muscle beta 1 syntrophin

Autosomal dominant (AD) pure spastic paraplegia (HSP) linked to locus SPG4 affects almost exclusively males in a large pedigree

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis

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