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GR.2 A deep intronic FGF14 GAA repeat expansion causes late-onset cerebellar ataxia
- D Pellerin, MC Danzi, C Wilke, M Renaud, S Fazal, M Dicaire, CK Scriba, C Ashton, C Yanick, D Beijer, A Rebelo, C Rocca, Z Jaunmuktane, JA Sonnen, R Larivière, D Genis, L Porcel, K Choquet, R Sakalla, S Provost, M Tétreault, SJ Reiling, S Nagy, V Nishadham, M Purushottam, S Vengalil, M Bardhan, A Nalini, Z Chen, J Mathieu, R Massie, CH Chalk, A Lafontaine, F Evoy, M Rioux, J Ragoussis, KM Boycott, M Dubé, A Duquette, H Houlden, G Ravenscroft, NG Laing, P Lamont, MA Saporta, R Schüle, L Schöls, R La Piana, M Synofzik, S Zuchner, B Brais
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- Journal:
- Canadian Journal of Neurological Sciences / Volume 50 / Issue s2 / June 2023
- Published online by Cambridge University Press:
- 05 June 2023, p. S46
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Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
High effective inbreeding coefficients correlate with morphological abnormalities in populations of South Australian koalas (Phascolarctos cinereus)
- Ayesha M. Seymour, Margaret E. Montgomery, Brian H. Costello, Sonja Ihle, Greg Johnsson, Barbara St. John, David Taggart, Bronwyn A. Houlden
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- Journal:
- Animal Conservation forum / Volume 4 / Issue 3 / August 2001
- Published online by Cambridge University Press:
- 29 August 2001, pp. 211-219
- Print publication:
- August 2001
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Koalas have undergone a series of sequential founding events on islands in south-eastern Australia in recent times. Populations in South Australia at the Eyre Peninsula and Mt Lofty Ranges were founded in the 1960s from a colony on Kangaroo Island. The Kangaroo Is. colony was derived from animals introduced to French Island from mainland Victoria over a century ago. In this study, we first use microsatellite markers to quantify levels of genetic variation within the South Australian koala populations and the relatively unperturbed Strzelecki Ranges population from mainland Victoria. This analysis revealed low levels of allelic diversity (1.7 ± 0.2 to 2.7 ± 0.5) and heterozygosity (0.208 ± 0.088 to 0.340 ± 0.110) in the three South Australian koala populations relative to the Strzelecki Ranges population, which has the highest levels of allelic diversity (4.7 ± 1.1) and heterozygosity (0.476 ± 0.122) in Victoria. Second, we measured the incidence of testicular aplasia, a unilateral or bilateral failure in testicular development, in the Eyre Peninsula and Kangaroo Is. populations, and in the ultimate founding population at French Is. Testicular aplasia was present at a frequency of 4.3% in French Is., 12.8% in Kangaroo Is. and 23.9% in the Eyre Peninsula, but was undetectable in the non-bottlenecked Pilliga State Forest population of New South Wales. The incidence of testicular aplasia correlated positively with effective inbreeding coefficients derived from heterozygosity values (0.13 ± 0.06 in the Pilliga State Forest, 0.57 ± 0.17 in French Is., 0.63 ± 0.12 on Kangaroo Is. and 0.77 ± 0.12 in the Eyre Peninsula), which may indicate inbreeding depression. These findings are of concern when evaluating the long-term conservation and viability of the South Australian koala populations, which may benefit from genetic augmentation in the future. Finally, unconfirmed reports suggested that animals from other states in Australia were introduced into the Mt Lofty Ranges population. Therefore, we quantified differentiation between the three South Australian populations and the Strzelecki Ranges and French Is. populations, based on microsatellites and mtDNA d-loop region variation. R-statistics and Goldstein's delta mu square distance revealed that differentiation at nuclear loci between populations paralleled known recent population history, except for the close relationship between Mt Lofty Ranges and French Is. This suggested a recent contribution to the Mt Lofty Ranges populations of animals derived from the French Is. translocation program. Furthermore, mtDNA d-loop analysis found no evidence of contributions to the gene pool from animals of New South Wales or Queensland stock, implying that the population was derived exclusively from Victorian stock.