Novel Genetic,Clinical, and Pathomechanistic Insights into TFG‐Associated Hereditary Spastic Paraplegia |
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| Authors: | Gaurav V. Harlalka Meriel E. McEntagart Neerja Gupta Anna E. Skrzypiec Mariusz W. Mucha Barry A. Chioza Michael A. Simpson Ajith Sreekantan‐Nair Anthony Pereira Sven Günther Amir Jahic Hamid Modarres Heather Moore‐Barton Richard C. Trembath Madhulika Kabra Emma L. Baple Seema Thakur Michael A. Patton Christian Beetz Robert Pawlak Andrew H. Crosby |
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| Affiliation: | 1. University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK;2. Medical Genetics Unit, Floor 0, Jenner Wing, St. George's University of London, London, UK;3. Division of Genetics, Department of Pediatrics, Old O.T. Block, All India Institute of Medical Sciences, New Delhi, India;4. Laboratory of Neuronal Plasticity and Behaviour, University of Exeter Medical School, University of Exeter, Exeter, UK;5. Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK;6. Department of Neurology, Atkinson Morley Wing, St. George's Hospital, London, UK;7. Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany;8. Department of Genetics and Fetal Medicine, Fortis La femme, New Delhi, India |
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| Abstract: | Hereditary spastic paraplegias (HSPs) are genetically and clinically heterogeneous axonopathies primarily affecting upper motor neurons and, in complex forms, additional neurons. Here, we report two families with distinct recessive mutations in TFG, previously suggested to cause HSP based on findings in a single small family with complex HSP. The first carried a homozygous c.317G>A (p.R106H) variant and presented with pure HSP. The second carried the same homozygous c.316C>T (p.R106C) variant previously reported and displayed a similarly complex phenotype including optic atrophy. Haplotyping and bisulfate sequencing revealed evidence for a c.316C>T founder allele, as well as for a c.316_317 mutation hotspot. Expression of mutant TFG proteins in cultured neurons revealed mitochondrial fragmentation, the extent of which correlated with clinical severity. Our findings confirm the causal nature of bi‐allelic TFG mutations for HSP, broaden the clinical and mutational spectra, and suggest mitochondrial impairment to represent a pathomechanistic link to other neurodegenerative conditions. |
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| Keywords: | hereditary spastic paraplegia founder allele mitochondria mutational hotspot TFG SPG57 |
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