Abstract
Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.
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Acknowledgements
We thank the members of the DNA and cell bank of the ICM, Federica Barreca, Emeline Mundwiller, Khalid El Hachimi and Delphine Bouteiller for their valuable contribution. This study was supported financially by the Agence Nationale de la Recherche (SPATAX-QUEST project, to Giovanni Stevanin), the Verum Foundation and Roger de Spoelberg Foundation (to Alexis Brice), the European Union (Neuromics projects, OMICS call, to Alexis Brice, Alexandra Durr and Giovanni Stevanin) and the National Institutes of Health (GM110567 to Anjon Audhya) and benefited from the Programme d’Investissement d’Avenir IHU-A-ICM. Liena Elsayed was the recipient of a Campus France and University of Khartoum fellowships.
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Elsayed, L., Mohammed, I., Hamed, A. et al. Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan. Eur J Hum Genet 25, 100–110 (2017). https://doi.org/10.1038/ejhg.2016.108
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DOI: https://doi.org/10.1038/ejhg.2016.108
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