Mannan, Ashraf U.

[["dc.bibliographiccitation.firstpage","99"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","European Journal of Neurology"],["dc.bibliographiccitation.lastpage","105"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Klimpe, Sven"],["dc.contributor.author","Zibat, Arne"],["dc.contributor.author","Zechner, Ulrich"],["dc.contributor.author","Wellek, B."],["dc.contributor.author","Shoukier, Moneef"],["dc.contributor.author","Sauter, Simone M."],["dc.contributor.author","Pantakani, Dasaradha Venkata Krishna"],["dc.contributor.author","Mannan, Ashraf U."],["dc.date.accessioned","2018-11-07T09:01:10Z"],["dc.date.available","2018-11-07T09:01:10Z"],["dc.date.issued","2011"],["dc.description.abstract","Background: Mutations in the SPG4/SPAST gene are the most common cause for hereditary spastic paraplegia (HSP). The splice-site mutations make a significant contribution to HSP and account for 17.4% of all types of mutations and 30.8% of point mutations in the SPAST gene. However, only few studies with limited molecular approach were conducted to investigate and decipher the role of SPAST splice-site mutations in HSP. Methods: A reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and quantitative allele-specific expression assay were performed. Results: We have characterized the consequence of two novel splice-site mutations (c.1493 + 1G > A and c.1414-1G > A) in the SPAST gene in two different families with pure HSP. The RT-PCR analysis revealed that both spastin mutations are indeed splice-site mutations and cause skipping of exon 12. Furthermore, RT-PCR data suggested that these splice-site mutations may cause leaky splicing. By means of a quantitative allele-specific expression assay, we could confirm that both splice-site mutations cause leaky splicing, as the relative expression of the exon 12-skipped transcript was reduced (21.1 +/- 3.6 compared to expected 50%). Conclusions: Our finding supports a \"threshold-effect-model\" for functional spastin in HSP. A higher level (78.8 +/- 3.9%) of functional spastin than the expected ratio of 50% owing to leaky splicing might cause late age at onset of HSP. Remarkably, we could show that a quantitative allele-specific expression assay is a simple and effective tool to evaluate the role of most types of spastin splice-site mutations in HSP."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft; Institute internal fund"],["dc.identifier.doi","10.1111/j.1468-1331.2010.03079.x"],["dc.identifier.isi","000285356300015"],["dc.identifier.pmid","20491894"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/24351"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell Publishing, Inc"],["dc.relation.issn","1351-5101"],["dc.title","Evaluating the effect of spastin splice mutations by quantitative allele-specific expression assay"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","93"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Neurogenetics"],["dc.bibliographiccitation.lastpage","103"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Mannan, Ashraf U."],["dc.contributor.author","Boehm, J."],["dc.contributor.author","Sauter, Simone M."],["dc.contributor.author","Rauber, A."],["dc.contributor.author","Byrne, P. C."],["dc.contributor.author","Neesen, J."],["dc.contributor.author","Engel, Wolfgang"],["dc.date.accessioned","2018-11-07T09:55:10Z"],["dc.date.available","2018-11-07T09:55:10Z"],["dc.date.issued","2006"],["dc.description.abstract","Spastin, an ATPase belonging to the AAA family of proteins is most commonly mutated in autosomal dominant hereditary spastic paraplegias (HSP). Spastin is a multifaceted protein with versatile role in cellular events, principally involved in microtubule dynamics. To gain further insight into the molecular function of spastin, we used the yeast two-hybrid approach to identify novel interacting partners of spastin. Using spastin as bait, we identified reticulon 1 (RTN1) and reticulon 3 (RTN3) as potential spastin interacting proteins. RTN1 and RTN3 belong to the reticulon (RTN) gene family, which are primarily expressed in the endoplasmic reticulum. Moreover, RTN1 is known to play a role in vesicular transport processes. Using in vitro and in vivo immunoprecipitation experiments, we were able to demonstrate that RTN1 interacts specifically with spastin. Intracellular distribution studies using immunostaining and overexpression of epitope-tagged protein revealed an obvious colocalization of spastin and RTN1 in discrete vesicles in the cytoplasm. Spastin mediates its interaction with RTN1 through its N-terminal region containing a microtubule-interacting and trafficking domain. It is interesting to note that the aberrant intracellular distribution of a truncated spastin protein was rescued by coexpression with RTN1, which highlights the physiological significance of this interaction. Our findings strengthen the hypothesis that disruption of intracellular vesicular transport processes could cause HSP. It is interesting to note that RTN1 is localized to 14q23.1 where SPG15 locus was mapped. Therefore, we considered RTN1 as a candidate gene for the SPG15 locus, but our mutational analysis possibly excludes RTN1 as causative gene."],["dc.identifier.doi","10.1007/s10048-006-0034-4"],["dc.identifier.isi","000237325600003"],["dc.identifier.pmid","16602018"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36690"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.relation.issn","1364-6745"],["dc.title","Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with reticulon 1 an endoplasmic reticulum protein"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","351"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","The American Journal of Human Genetics"],["dc.bibliographiccitation.lastpage","357"],["dc.bibliographiccitation.volume","79"],["dc.contributor.author","Mannan, Ashraf U."],["dc.contributor.author","Krawen, Philip"],["dc.contributor.author","Sauter, Simone M."],["dc.contributor.author","Boehm, Johann"],["dc.contributor.author","Chronowska, Agnieszka"],["dc.contributor.author","Paulus, Walter J."],["dc.contributor.author","Neesen, Juergen"],["dc.contributor.author","Engel, Wolfgang"],["dc.date.accessioned","2018-11-07T09:26:29Z"],["dc.date.available","2018-11-07T09:26:29Z"],["dc.date.issued","2006"],["dc.description.abstract","Spastin, the most commonly mutated protein in the autosomal dominant form of hereditary spastic paraplegia (ADHSP) has been suggested to be involved in vesicular cargo trafficking; however, a comprehensive function of spastin has not yet been elucidated. To characterize the molecular function of spastin, we used the yeast two-hybrid approach to identify new interacting partners of spastin. Here, we report ZFYVE27, a novel member of the FYVE-finger family of proteins, as a specific spastin-binding protein, and we validate the interaction by both in vivo coimmunoprecipitation and colocalization experiments in mammalian cells. More importantly, we report a German family with AD-HSP in which ZFYVE27 (SPG33) is mutated; furthermore, we demonstrate that the mutated ZFYVE27 protein shows an aberrant intracellular pattern in its tubular structure and that its interaction with spastin is severely affected. We postulate that this specific mutation in ZFYVE27 affects neuronal intracellular trafficking in the corticospinal tract, which is consistent with the pathology of HSP."],["dc.identifier.doi","10.1086/504927"],["dc.identifier.isi","239040400016"],["dc.identifier.pmid","16826525"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/30313"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Univ Chicago Press"],["dc.relation.issn","0002-9297"],["dc.title","ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","268"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Clinical Genetics"],["dc.bibliographiccitation.lastpage","272"],["dc.bibliographiccitation.volume","73"],["dc.contributor.author","Pantakani, Dasaradha Venkata Krishna"],["dc.contributor.author","Zechner, Ulrich"],["dc.contributor.author","Arygriou, L."],["dc.contributor.author","Pauli, Silke"],["dc.contributor.author","Sauter, Simone M."],["dc.contributor.author","Mannan, Ashraf U."],["dc.date.accessioned","2018-11-07T11:17:25Z"],["dc.date.available","2018-11-07T11:17:25Z"],["dc.date.issued","2008"],["dc.description.abstract","The SPG4 gene is frequently mutated in autosomal dominant form of hereditary spastic paraplegia (HSP). We report that the compound heterozygous sequence variants S44L, a known polymorphism, and c.1687G > A, a novel mutation in SPG4 cause a severe form of HSP in a patient. The family members carrying solely c.1687G > A mutation are asymptomatic for HSP. The reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the c.1687G > A mutation is a splice site mutation and causes skipping of the exon 15 of spastin. Furthermore, quantification of RT-PCR products by sequencing and quantification of allele-specific expression by pyrosequencing assay revealed that c.1687G > A is a leaky or hypomorphic splice site mutation. At the protein level, c.1687G > A mutation in SPG4 leads to E563K substitution. In ex vivo study, about 10% of cells expressing E563K mutant spastin showed filamentous expression pattern, suggesting a hypomorphic effect at the protein level. Collectively, our results suggest that S44L in association with c.1687G > A (E563K) drops the functional level of spastin below a threshold limit sufficient to manifest HSP."],["dc.identifier.doi","10.1111/j.1399-0004.2007.00953.x"],["dc.identifier.isi","000252929000012"],["dc.identifier.pmid","18190593"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/54802"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Blackwell Publishing"],["dc.relation.issn","0009-9163"],["dc.title","Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","187"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","European Journal of Human Genetics"],["dc.bibliographiccitation.lastpage","194"],["dc.bibliographiccitation.volume","17"],["dc.contributor.author","Shoukier, Moneef"],["dc.contributor.author","Neesen, Juergen"],["dc.contributor.author","Sauter, Simone M."],["dc.contributor.author","Argyriou, Loukas"],["dc.contributor.author","Doerwald, Nadine"],["dc.contributor.author","Pantakani, Dasaradha Venkata Krishna"],["dc.contributor.author","Mannan, Ashraf U."],["dc.date.accessioned","2018-11-07T08:32:59Z"],["dc.date.available","2018-11-07T08:32:59Z"],["dc.date.issued","2009"],["dc.description.abstract","The SPAST gene encoding for spastin plays a central role in the genetically heterogeneous group of diseases termed hereditary spastic paraplegia (HSP). In this study, we attempted to expand and refine the genetic and phenotypic characteristics of SPAST associated HSP by examining a large cohort of HSP patients/families. Screening of 200 unrelated HSP cases for mutations in the SPAST gene led to detection of 57 mutations (28.5%), of which 47 were distinct and 29 were novel mutations. The distribution analysis of known SPAST mutations over the structural domains of spastin led to the identification of several regions where the mutations were clustered. Mainly, the clustering was observed in the AAA (ATPases associated with diverse cellular activities) domain; however, significant clustering was also observed in the MIT (microtubule interacting and trafficking), MTBD (microtubule-binding domain) and an N-terminal region (228-269 residues). Furthermore, we used a previously generated structural model of spastin as a framework to classify the missense mutations in the AAA domain from the HSP patients into different structural/functional groups. Our data also suggest a tentative genotype-phenotype correlation and indicate that the missense mutations could cause an earlier onset of the disease."],["dc.identifier.doi","10.1038/ejhg.2008.147"],["dc.identifier.isi","000262499600010"],["dc.identifier.pmid","18701882"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/17465"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","1018-4813"],["dc.title","Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]