Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia

作者：Harlalka Gaurav V; McEntagart Meriel E; Gupta Neerja; Skrzypiec Anna E; Mucha Mariusz W; Chioza Barry A; Simpson Michael A; Sreekantan Nair Ajith; Pereira Anthony; Guenther Sven; Jahic Amir; Modarres Hamid; Moore Barton Heather; Trembath Richard C; Kabra Madhulika; Baple Emma L; Thakur Seema; Patton Michael A; Beetz Christian^*; Pawlak Robert; Cro**y Andrew H^*

来源：Human Mutation, 2016, 37(11): 1157-1161.

DOI：10.1002/humu.23060

• hereditary spastic paraplegia
• founder allele
• mitochondria
• mutational hotspot
• TFG
• SPG57

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.

• 出版日期2016-11
• 单位河北医科大学