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Novel Genetic, Clinical, and Pathomechanistic Insights into TFG‐Associated Hereditary Spastic Paraplegia
Author(s) -
Harlalka Gaurav V.,
McEntagart Meriel E.,
Gupta Neerja,
Skrzypiec Anna E.,
Mucha Mariusz W.,
Chioza Barry A.,
Simpson Michael A.,
SreekantanNair Ajith,
Pereira Anthony,
Günther Sven,
Jahic Amir,
Modarres Hamid,
MooreBarton Heather,
Trembath Richard C.,
Kabra Madhulika,
Baple Emma L.,
Thakur Seema,
Patton Michael A.,
Beetz Christian,
Pawlak Robert,
Crosby Andrew H.
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23060
Subject(s) - hereditary spastic paraplegia , biology , genetics , phenotype , haplotype , allele , mutation , mutant , mitochondrial dna , missense mutation , gene
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.