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Screening of ARHSP-TCC Patients Expands the Spectrum of SPG11 Mutations and Includes a Large Scale Gene Deletion

DENORA, Paola S.; SCHLESINGER, David; CASALI, Carlo; KOK, Fernando; TESSA, Alessandra; BOUKHRIS, Amir; AZZEDINE, Hamid; DOTTI, Maria Teresa; BRUNO, Claudio; TRUCHETTO, Jeremy; BIANCHERI, Roberta; FEDIRKO, Estelle; ROCCO, Maja Di; BUENO, Clarissa; MALANDRI
Fonte: WILEY-LISS Publicador: WILEY-LISS
Tipo: Artigo de Revista Científica
ENG
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Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing. (C) 2008 Wiley-Liss...

Conectoma cerebral : aplicações de imageamento por ressonância magnética nuclear em neurociências = Brain connectome : aplications of nuclear magnetic resonance imaging in neurosciences; Brain connectome : aplications of nuclear magnetic resonance imaging in neurosciences

Fabricio Ramos Silvestre Pereira
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 22/07/2013 PT
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O conectoma cerebral refere-se ao mapeamento dos circuitos neurais com os objetivos de 1) identificar regiões que dão suporte às atividades mentais e comportamentais, e 2) detectar alterações nesses circuitos que levam a distúrbios de ordem psiquiátrica e neurológica. Na prática, os estudos de conectoma cerebral consistem na integração de técnicas multimodais de imageamento como ressonância magnética (RM), eletroencefalograma (EEG) e magnetoencefalograma (MEG) com o intuito de estimar os tipos e os níveis de conexão entre regiões cerebrais remotas. Essa "conectividade" entre regiões cerebrais é geralmente classificada em três tipos: anatômica, funcional e efetiva. No presente trabalho, as técnicas de conectividade, usando dados de MR, foram aplicadas na comparação de grupos saudáveis e patológicos. Pela técnica de conectividade anatômica observou-se anomalias na substância branca de pacientes com mutação no gene SPG11. Essa anomalias foram detectadas através da redução da anisotropia fracional (FA) e aumento da difusividade média (MD), difusividade radial (RD) e difusividade axial (AD) em regiões subcorticais dos lobos temporal e frontal, bem como no giro do cíngulo, cuneus striatum, corpo caloso e tronco cerebral. Tais achados indicam que o dano neuronal é mais difuso do que indicava a literatura. Um segundo estudo de conectividade anatômica demonstrou que esses índices de difusividade não foram robustos para diferenciar idosos com e sem diagnóstico de depressão indicando a necessidade de avanços na formulação de novos índices com maior sensibilidade. A técnica de conectividade funcional foi empregada em três estudos. No primeiro...

Identification of the SPG15 Gene, Encoding Spastizin, as a Frequent Cause of Complicated Autosomal-Recessive Spastic Paraplegia, Including Kjellin Syndrome

Hanein, Sylvain; Martin, Elodie; Boukhris, Amir; Byrne, Paula; Goizet, Cyril; Hamri, Abdelmadjid; Benomar, Ali; Lossos, Alexander; Denora, Paola; Fernandez, José; Elleuch, Nizar; Forlani, Sylvie; Durr, Alexandra; Feki, Imed; Hutchinson, Michael; Santorel
Fonte: American Society of Human Genetics Publicador: American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
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16.86%
Hereditary spastic paraplegias (HSPs) are genetically and phenotypically heterogeneous disorders. Both “uncomplicated” and “complicated” forms have been described with various modes of inheritance. Sixteen loci for autosomal-recessive “complicated” HSP have been mapped. The SPG15 locus was first reported to account for a rare form of spastic paraplegia variably associated with mental impairment, pigmented maculopathy, dysarthria, cerebellar signs, and distal amyotrophy, sometimes designated as Kjellin syndrome. Here, we report the refinement of SPG15 to a 2.64 Mb genetic interval on chromosome 14q23.3-q24.2 and the identification of ZFYVE26, which encodes a zinc-finger protein with a FYVE domain that we named spastizin, as the cause of SPG15. Six different truncating mutations were found to segregate with the disease in eight families with a phenotype that included variable clinical features of Kjellin syndrome. ZFYVE26 mRNA was widely distributed in human tissues, as well as in rat embryos, suggesting a possible role of this gene during embryonic development. In the adult rodent brain, its expression profile closely resembled that of SPG11, another gene responsible for complicated HSP. In cultured cells, spastizin colocalized partially with markers of endoplasmic reticulum and endosomes...

SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia (HSP)

Paisan-Ruiz, Coro; Dogu, Okan; Yilmaz, Arda; Houlden, Henry; Singleton, Andrew
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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16.86%

Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish

Southgate, Laura; Dafou, Dimitra; Hoyle, Jacqueline; Li, Nan; Kinning, Esther; Critchley, Peter; Németh, Andrea H.; Talbot, Kevin; Bindu, Parayil S.; Sinha, Sanjib; Taly, Arun B.; Raghavendra, Seetharam; Müller, Ferenc; Maher, Eamonn R.; Trembath, Richa
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
EN
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28.57%
Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5′ RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities...

Expanding the Clinical Spectrum of SPG11 Gene Mutations in Recessive Hereditary Spastic Paraplegia with Thin Corpus Callosum

Aleem, Alice Abdel; Abu-Shahba, Nourhan; Swistun, Dominika; Silhavy, Jennifer; Bielas, Stephanie L.; Sattar, Shifteh; Gleeson, Joseph G.; Zaki, Maha
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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28.42%
Hereditary spastic paraplegia (HSP) represents a large group of neurological disorders characterized by progressive spasticity of the lower limbs. One subtype of HSP shows an autosomal recessive form of inheritance with this corpus callosum (ARHSP-TCC), and displays genetic heterogeneity with four known loci. We identified a consanguineous Egyptian family with five affected individuals with ARHSP-TCC. We found linkage to the SPG11 locus and identified a novel homozygous p.Q498X stop codon mutation in exon 7 in the SPG11 gene encoding Spatacsin. Cognitive impairment and polyneuropathy, reported as frequent in SPG11, were not evident. This family supports the importance of SPG11 as a frequent cause for ARHSP-TCC, and expands the clinic SPG11 spectrum.

NEUROTRANSMITTER ABNORMALITIES AND RESPONSE TO SUPPLEMENTATION IN SPG11

Vanderver, Adeline; Tonduti, Davide; Auerbach, Sarah; Schmidt, Johanna L.; Parikh, Sumit; Gowans, Gordon C.; Jackson, Kelly E.; Brock, Pamela L.; Patterson, Marc; Nehrebecky, Michelle; Godfrey, Rena; Zein, Wadih M.; Gahl, William; Toro, Camilo
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
16.86%

SPG11 Presenting with Tremor

Schneider, Susanne A.; Mummery, Catherine J.; Mehrabian, Mohadeseh; Houlden, Henry; Bain, Peter G.
Fonte: Columbia University Libraries/Information Services Publicador: Columbia University Libraries/Information Services
Tipo: Artigo de Revista Científica
Publicado em 14/09/2012 EN
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Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15

Hirst, Jennifer; Borner, Georg H. H.; Edgar, James; Hein, Marco Y.; Mann, Matthias; Buchholz, Frank; Antrobus, Robin; Robinson, Margaret S.
Fonte: The American Society for Cell Biology Publicador: The American Society for Cell Biology
Tipo: Artigo de Revista Científica
Publicado em 15/08/2013 EN
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The adaptor protein complex AP-5 is stably associated with the hereditary spastic paraplegia proteins SPG11 and SPG15 in an apparently equimolar ratio to form a new type of coat. Results suggest that SPG15 facilitates the docking of the coat onto late endosomal/lysosomal membranes and that SPG11 (possibly together with SPG15) acts as a scaffold.

Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11

Renvoisé, Benoît; Chang, Jaerak; Singh, Rajat; Yonekawa, Sayuri; FitzGibbon, Edmond J; Mankodi, Ami; Vanderver, Adeline; Schindler, Alice B; Toro, Camilo; Gahl, William A; Mahuran, Don J; Blackstone, Craig; Pierson, Tyler Mark
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
EN
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16.86%

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

Chang, Jaerak; Lee, Seongju; Blackstone, Craig
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
EN
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16.86%
Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate. Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.

C19orf12 mutation leads to Karak pallido-pyramidal syndrome

Kruer, Michael C.; Salih, Mustafa A.; Mooney, Catherine; Alzahrani, Jawahir; Elmalik, Salah A.; Kabiraj, Mohammad M.; Khan, Arif O.; Paudel, Reema; Houlden, Henry; Azzedine, Hamid; Alkuraya, Fowzan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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16.86%
Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. In particular, mutations in PLA2G6 have been identified in patients with Karak syndrome, a neurodegenerative disorder that features ataxia, dystonia-parkinsonism, dementia and spasticity with neuroradiologic evidence of cerebellar atrophy and/or brain iron deposition. Some patients with phenotypic Karak syndrome do not have demonstrable mutations in PLA2G6. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with Karak syndrome, we identified a homozygous p.G53R mutation in C19orf12. Our findings expand the phenotypic spectrum associated with C19orf12 mutations.

Identification of Novel Mutations in Spatacsin and Apolipoprotein B Genes in a Patient with Spastic Paraplegia and Hypobetalipoproteinemia

Peddareddygari, Leema Reddy; Grewal, Raji P.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
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17.56%
Complicated hereditary spastic paraplegia (HSP) presents with complex neurological and nonneurological manifestations. We report a patient with autosomal recessive (AR) HSP in whom laboratory investigations revealed hypobetalipoproteinemia raising the possibility of a shared pathophysiology of these clinical features. A lipid profile of his parents disclosed a normal maternal lipid profile. However, the paternal lipid profile was similar to that of the patient suggesting autosomal dominant transmission of this trait. Whole exome sequence analysis was performed and novel mutations were detected in both the SPG11 and the APOB genes. Genetic testing of the parents showed that both APOB variants were inherited from the father while the SPG11 variants were inherited one from each parent. Our results indicate that, in this patient, the hypobetalipoproteinemia and spastic paraplegia are unrelated resulting from mutations in two independent genes. This clinical study provides support for the use of whole exome sequencing as a diagnostic tool for identification of mutations in conditions with complex presentations.

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J. Christopher; Franzka, Patricia; Huebner, Antje K.; Kessels, Michael M.; Biskup, Christoph; Jentsch, Thomas J.; Qualmann, B
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 18/08/2015 EN
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27.93%
Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo...

Mutationsanalysen bei Patienten mit hereditärer spastischer Spinalparalyse Typ 11 (SPG11)

Engel, Anna
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
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Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia

Pérez-Brangulí, Francesc; Mishra, Himanshu K.; Prots, Iryna; Havlicek, Steven; Kohl, Zacharias; Saul, Domenica; Rummel, Christine; Dorca-Arevalo, Jonatan; Regensburger, Martin; Graef, Daniela; Sock, Elisabeth; Blasi, Juan; Groemer, Teja W.; Schlötzer-S
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
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Hereditary spastic paraplegias are a group of inherited motor neuron diseases characterized by progressive paraparesis and spasticity. Mutations in the spastic paraplegia gene SPG11, encoding spatacsin, cause an autosomal-recessive disease trait; however, the precise knowledge about the role of spatacsin in neurons is very limited. We for the first time analyzed the expression and function of spatacsin in human forebrain neurons derived from human pluripotent stem cells including lines from two SPG11 patients and two controls. SPG11 patients'-derived neurons exhibited downregulation of specific axonal-related genes, decreased neurite complexity and accumulation of membranous bodies within axonal processes. Altogether, these data point towards axonal pathologies in human neurons with SPG11 mutations. To further corroborate spatacsin function, we investigated human pluripotent stem cell-derived neurons and mouse cortical neurons. In these cells, spatacsin was located in axons and dendrites. It colocalized with cytoskeletal and synaptic vesicle (SV) markers and was present in synaptosomes. Knockdown of spatacsin in mouse cortical neurons evidenced that the loss of function of spatacsin leads to axonal instability by downregulation of acetylated tubulin. Finally...

Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients

de Bot, Susanne T; Burggraaff, Rogier C; Herkert, Johanna C; Schelhaas, Helenius J; Post, Bart; Diekstra, Adinda; van Vliet, Reinout O; van der Knaap, Marjo S; Kamsteeg, Erik-Jan; Scheffer, Hans; van de Warrenburg, Bart P; Verschuuren-Bemelmans, Corien C;
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
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Although SPG11 is the most common complicated hereditary spastic paraplegia, our knowledge of the long-term prognosis and life expectancy is limited. We therefore studied the disease course of all patients with a proven SPG11 mutation as tested in our laboratory, the single Dutch laboratory providing SPG11 mutation analysis, between 1 January 2009 and 1 January 2011. We identified nine different SPG11 mutations, four of which are novel, in nine index patients. Eighteen SPG11 patients from these nine families were studied by means of a retrospective chart analysis and additional interview/examination. Ages at onset were between 4 months and 14 years; 39% started with learning difficulties rather than gait impairment. Brain magnetic resonance imaging showed a thin corpus callosum and typical periventricular white matter changes in the frontal horn region (known as the ‘ears-of the lynx'-sign) in all. Most patients became wheelchair bound after a disease duration of 1 to 2 decades. End-stage disease consisted of loss of spontaneous speech, severe dysphagia, spastic tetraplegia with peripheral nerve involvement and contractures. Several patients died of complications between ages 30 and 48 years, 3–4 decades after onset of gait impairment. Other relevant features during the disease were urinary and fecal incontinence...