Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p

Hazan, Jamilé; Fontaine, Bertrand; Bruyn, R.P.M.; Lamy, Catherine; Deutekom, J.C.T. van; Rime, Clalre-Sophie; Dürr, Alexandra; Melkl, Judith; Lyon-Caen, O.; Agid, Yves; Münnich, Arnold; Padberg, George W.; Recondo, J. De; Frants, Rune R.; Brice, Alexis; Welssenbach, Jean

doi:10.1093/hmg/3.9.1569

Cited by 123 publications

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“…1 Several types of HSP have been mapped to different loci, demonstrating extensive genetic heterogeneity. AD-HSP has been mapped to chromosome 14q11.2-q24.3 (SPG3) in French, American, German and Tibetan families, [2][3][4][5] to chromosome 2p21-p24 (SPG4) in French, Dutch, North American, Tunisian, Belgian and German families, 3,[6][7][8] to 15q (SPG6) in one family of Irish descent, 9 to 8q23-24 (SPG8) in a North American kindred of German descent and in an English family 10,11 and to 12q13 (SPG10) in an English family. 12 There must be at least one further AD-HSP locus, since in one family linkage to all these five loci has been excluded.…”

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confidence: 99%

Hereditary spastic paraplegia caused by mutations in the SPG4 gene

et al. 2000

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Section: Introductionmentioning

confidence: 99%

Hereditary spastic paraplegia caused by mutations in the SPG4 gene

et al. 2000

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“…Autosomal dominant 'pure' HSP has been linked to three distinct loci on chrosomosome 2p (SPG4), 8,9 chromosome 14q (SPG3) 10 and chromosome 15p (SPG6). 11 To date approximately 45% of families remain unlinked, indicating the presence of at least one other locus.…”

Section: Introductionmentioning

confidence: 99%

Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance

et al. 1998

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We report linkage of a family affected with autosomal dominant hereditary spastic paraparesis (HSP) and/or cognitive impairment to the HSP locus on chromosome 2p. To date all families linked to this locus have been affected with 'pure' HSP. The specific pattern of cognitive impairment in this family is characterised primarily by deficits in visuo-spatial functions. We also present genetic studies that indicate variable expression and low or delayed penetrance. We have constructed a haplotype flanked by polymorphic markers D2S400 and D2S2331 that was present in 12 individuals affected with spastic paraparesis. The severity of spasticity varied markedly among these individuals. In addition four of these individuals (aged 62-70) also had a specific form of cognitive impairment. The disease haplotype was also present in an individual (age 57) who had an identical pattern of cognitive impairment as the only sign of the disease supporting the hypothesis that spastic paraparesis and cognitive impairment are the result of variable expression of a single gene (rather than a co-incidental occurrence). Haplotype reconstruction for all participating family members revealed the presence of this disease haplotype in six individuals who had normal neurological and neuropsychological examinations. All six are below the maximal age of onset in the family -60 years. This is evidence for low or late penetrance of the AD HSP gene in this family. The identification of normal individuals carrying the disease haplotype demonstrates the importance of genetic studies in combination with clinical examination when counselling at risk family members.

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“…Work in C. elegans suggests that microtubule severing by Mei-1 katanin increases the steady-state number of microtubules during both meiosis and mitosis (52) but increases the total polymer mass in meiotic spindles only (53). Genetic mutations in the microtubule-severing protein spastin show it to be responsible for hereditary spastic paraplegia, which is characterized by spasticity and weakness in the lower limbs (54). Spastin is involved in microtubule dynamics, and overexpression of spastin results in disassembly of microtubules, suggesting an underlying mechanism for hereditary spastic paraplegia pathogenesis (55).…”

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The Cul3/Klhdc5 E3 Ligase Regulates p60/Katanin and Is Required for Normal Mitosis in Mammalian Cells

Cummings

Bentley

Perdue

et al. 2009

Journal of Biological Chemistry

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The proper regulation of factors involved in mitosis is crucial to ensure normal cell division. Levels and activities of proteins are regulated in many ways, one of which is ubiquitin-mediated protein degradation. E3 ubiquitin ligases are involved in targeting specific substrates for degradation by facilitating their ubiquitination. In seeking to elucidate additional biological roles for Cul3 we performed a two-hybrid screen and identified Ctb9/ KLHDC5 as a Cul3-interacting protein. Overexpression of Ctb9/KLHDC5 resulted in an increase in microtubule density as well as persistent microtubule bridges between post-mitotic cells. Conversely, down-regulation of Ctb9/KLHDC5 showed a pronounced reduction in microtubule density. Based on these observations, we examined the interactions between Cul3, Ctb9/KLHDC5, and the microtubule-severing protein, p60/katanin. Here we show that p60/katanin interacts with a complex consisting of Cul3 and Ctb9/KLHDC5, which results in ubiquitin laddering of p60/katanin. Also, Cul3-deficient cells or Ctb9/KLHDC5-deficient cells show an increase in p60/katanin levels, indicating that Cul3/Ctb9/KLHDC5 is required for efficient p60/katanin removal. We demonstrate a novel regulatory mechanism for p60/katanin that occurs at the level of targeted proteolysis to allow normal mitotic progression in mammalian cells.Due to the irreversible nature of protein degradation, ubiquitin-mediated proteolysis is an effective method to sequentially order cell cycle events. During ubiquitin-mediated protein degradation, the E1 5 ubiquitin-activating enzyme forms an ATP-dependent thioester bond with a ubiquitin molecule. The activated ubiquitin is subsequently transferred to an E2 ubiquitin-conjugating enzyme, which can either directly attach ubiquitin onto its substrate or act in concert with an E3 ubiquitin ligase to achieve the same end (1, 2). The E3 serves a dual function in recruiting the E2 ubiquitin-conjugating enzyme to the substrate and in positioning the two in close proximity.

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Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p

Cited by 123 publications

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Hereditary spastic paraplegia caused by mutations in the SPG4 gene

Hereditary spastic paraplegia caused by mutations in the SPG4 gene

Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance

The Cul3/Klhdc5 E3 Ligase Regulates p60/Katanin and Is Required for Normal Mitosis in Mammalian Cells

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