New genetic type of Pure Hereditary Spastic Paraplegia
محل انتشار: هشتمین کنگره علوم اعصاب و پایه و بالینی
سال انتشار: 1398
نوع سند: مقاله کنفرانسی
زبان: انگلیسی
مشاهده: 350
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شناسه ملی سند علمی:
NSCMED08_090
تاریخ نمایه سازی: 15 دی 1398
چکیده مقاله:
Background and Aim : Hereditary spastic paraplegia (HSP) is a heterogenous group of monogenic neurodegenerative diseases. Of 80 identified genes/loci, each gene mutations cause a distinct type of HSP. Genetic and clinical overlap have been reported between HSP and other neurological diseases, yet over 50% of HSP patients remain genetically unknown.Methods : A total of 696 HSP patients from 431 families were recruited in the study. To identify novel genes involved in HSP, we performed whole exome sequencing (WES) for 383 HSP patients who were genetically undiagnosed. In addition, 251 unrelated healthy individuals went through WES as controls. Multiple databases and tools were applied to evaluate the effect of mutations.Results : Two unrelated patients, who presented pure HSP with normal brain and spine MRI, with very rare compound heterozygous SPTAN1 mutations were identified; one harbored the c.2572G> T p.(Ala858Ser) and c.4283C> G p.(Ala1428Gly) mutations, and the second also harbored the c.2572G> T p.(Ala858Ser) mutation, and an additional mutation, c.6990G> C p.(Met2330Ile). Validation and further segregation of the suspected pathogenic variants were performed using Sanger sequencing. SPTAN1 gene was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed versus expected number of loss-of-function variants (8 vs. 142.7, p<5x10-15). All three mutations were predicted to be deleterious by CADD and MutationTaster, and were located in highly conserved amino acids with all GERP++ scores > 4.7. Protein–protein interaction network using STRING revealed that SPTAN1 protein closely interacts with other HSP-related proteins (CAPN1, L1CAM, ENTPD1). SWISS-MODEL was used to generate homology models of human spectrin repeats and validated the effect of these variants on SPTAN1 function and structure. We have found previously described mouse, zebrafish and rat animal models of SPTAN1 disruption, all consistently showing axonal degeneration, fitting the pathological features of HSP.Conclusion : Our results suggest that SPTAN1 may cause autosomal recessive pure HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.
کلیدواژه ها:
نویسندگان
Mehrdad Asghari Estiar
Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada
Etienne Leveiller
Faculty of Medicine, McGill University, Montréal, QC, Canada
Lynne Krohn
Department of Human Genetics, McGill University, Montréal, QC, Canada
Dan Spiegelman
Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
Alexander Dionne-Laporte
Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
Nicolas Dupre
Division of Neurosciences, CHU de Québec, Université Laval, Québec City, QC, Canada