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| Antonio Orlacchio |
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Laboratorio di Neurogenetica, IRCCS S.Lucia, Via Ardeatina 354, Rome, Italy, 00179
e-mail: a.orlacchio@hsantalucia.it |
Poster Presentation: |
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| A NOVEL MUTATION IN SPASTIN GENE DEMONSTRATED SPASTIC PARAPLEGIA AND THIN CORPUS CALLOSUM. |
| A.Orlacchio (a) T.Kawarai (b) W.Meschino (d) A.Totaro (a) P.St George-Hyslop (b) A.Errico (c) E.Rugarli (c) G.Bernardi (a) | |
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(a) Lab.Neurogenetica, IRCCS Santa Lucia, Rome, Italy; (b) CRND, U.Toronto, Canada; (c) TIGEM, Naples, Italy; (d) Dept.Medical Genetics, North York Hospital, Canada |
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| The study of the hypoplasy or the agenesis of the corpus callosum observed in various neurological diseases may be interesting in further understanding the brain structure in development. To date, several genetic factors related to neurological deficits including mal-development of the corpus callosum have been identified in human and mouse. For example, L1 adhesion molecule in the X-linked mental retardation syndrome CRASH (acronym for corpus callosum agenesis, retardation, aphasia, spastic paraplegia, hydrocephalus) and Emx1 mutant mice with 129/Sv background. Recent genetic studies of the hereditary spastic paraplegia (HSP) revealed a new insight of the brain structure in corpus callosum. Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSP with TCC) has been mapped on chromosome 15q13-15 locus. Complication of thin corpus callosum is also observed in other ARHSP cases unlinked to ARHSP with TCC locus. Genetic mechanism of thin corpus callosum accompanying HSP remains unknown. We identified a novel mutation Asn386Ser in the Spastin gene in nine autosomal dominant HSP families originated from south of Scotland. Thin corpus callosum was observed in two affected members from unrelated families but never observed in other affected members. This suggests that the mutant Spastin interacts with other genetic factor(s) or environmental factor(s) leading to hypoplasy in corpus callosum in addition to neurodegeneration in cortico-spinal tract. To investigate the underlying molecular mechanisms caused by the novel mutation in the Spastin gene, we expressed the mutant Spastin in cultured cells and examined the potential pathological mechanisms affecting the cytoskeletal protein. Expression of the mutant Spastin Asn386Ser in Cos-7 and Hela cells showed constitutive binding to microtubules and induced a redistribution of the microtubule cytoskeleton, demonstrating altered microtubule dynamics. The result provided an evidence of mutant Spastin affecting the microtubule dynamics, but succeeding molecular mechanisms of neurodegeneration in cortico-spinal tract and mal-development of corpus callosum remain unknown. Spastin belongs to AAA (ATPases Associated with diverse cellular Activities) protein family and may have a diverse effect in neuronal cells. Further analysis of clinical mutations in the Spastin gene and the identification of the “disease gene” in ARHSP with TCC will reveal molecular regulation in development of corpus callosum and neurodegeneration in long axons.
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