title: Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia.
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.
authors: University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, UK.
authors: Gaurav V
authors: GV
authors: Harlalka
authors: Medical Genetics Unit, Floor 0, Jenner Wing, St. George's University of London, Cranmer Terrace, London, UK.
authors: Meriel E
authors: ME
authors: McEntagart
authors: Division of Genetics, Department of Pediatrics, Old O.T. Block, All India Institute of Medical Sciences, New Delhi, India.
authors: Neerja
authors: N
authors: Gupta
authors: Laboratory of Neuronal Plasticity and Behaviour, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Anna E
authors: AE
authors: Skrzypiec
authors: Laboratory of Neuronal Plasticity and Behaviour, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Mariusz W
authors: MW
authors: Mucha
authors: University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, UK.
authors: Barry A
authors: BA
authors: Chioza
authors: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK.
authors: Michael A
authors: MA
authors: Simpson
authors: University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, UK.
authors: Ajith
authors: A
authors: Sreekantan-Nair
authors: Department of Neurology, Atkinson Morley Wing, St. George's Hospital, Tooting, London, UK.
authors: Anthony
authors: A
authors: Pereira
authors: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors: Sven
authors: S
authors: Günther
authors: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors: Amir
authors: A
authors: Jahic
authors: Department of Neurology, Atkinson Morley Wing, St. George's Hospital, Tooting, London, UK.
authors: Hamid
authors: H
authors: Modarres
authors: Medical Genetics Unit, Floor 0, Jenner Wing, St. George's University of London, Cranmer Terrace, London, UK.
authors: Heather
authors: H
authors: Moore-Barton
authors: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK.
authors: Richard C
authors: RC
authors: Trembath
authors: Division of Genetics, Department of Pediatrics, Old O.T. Block, All India Institute of Medical Sciences, New Delhi, India.
authors: Madhulika
authors: M
authors: Kabra
authors: University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, UK.
authors: Emma L
authors: EL
authors: Baple
authors: Department of Genetics and Fetal Medicine, Fortis La femme, S-549, New Delhi, India.
authors: Seema
authors: S
authors: Thakur
authors: Medical Genetics Unit, Floor 0, Jenner Wing, St. George's University of London, Cranmer Terrace, London, UK.
authors: Michael A
authors: MA
authors: Patton
authors: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany. christian.beetz@med.uni.jena.de.
authors: Christian
authors: C
authors: Beetz
authors: Laboratory of Neuronal Plasticity and Behaviour, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Robert
authors: R
authors: Pawlak
authors: University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, UK.
authors: Andrew H
authors: AH
authors: Crosby
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000473:pathology; D020125:Mutation, Missense; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D033921:Vesicular Transport Proteins
chemical_list: D011506:Proteins; C096163:TFG protein, human; D033921:Vesicular Transport Proteins
keywords: SPG57; TFG; founder allele; hereditary spastic paraplegia; mitochondria; mutational hotspot