Brief Report: Novel Genetic, Clinical and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia.

2.50
Hdl Handle:
http://hdl.handle.net/11287/618725
Title:
Brief Report: Novel Genetic, Clinical and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia.
Authors:
Harlalka, Gaurav V.; McEntagart, M. E.; Gupta, N.; Skrzypiec, A.; Mucha, M.; Chioza, Barry A.; Simpson, M. A.; Sreekantan-Nair, A.; Pereira, A.; Günther, S.; Jahic, A.; Modarres, H.; Moore-Barton, H.; Trembath, R.C.; Kabra, M.; Baple, E. L.; Thakur, S.; Patton, M. A.; Beetz, C.; Pawlak, R.; Crosby, Andrew H.
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. This article is protected by copyright. All rights reserved.
Citation:
Brief Report: Novel Genetic, Clinical and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia. 2016 Nov;37(11):1157-1161 Hum. Mutat.
Publisher:
Wiley
Journal:
Human Mutation
Issue Date:
5-Aug-2016
URI:
http://hdl.handle.net/11287/618725
DOI:
10.1002/humu.23060
PubMed ID:
27492651
Additional Links:
http://dx.doi.org/10.1002/humu.23060
Type:
Journal Article
Language:
en
ISSN:
1098-1004
Appears in Collections:
Honorary contracts publications; 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorHarlalka, Gaurav V.en
dc.contributor.authorMcEntagart, M. E.en
dc.contributor.authorGupta, N.en
dc.contributor.authorSkrzypiec, A.en
dc.contributor.authorMucha, M.en
dc.contributor.authorChioza, Barry A.en
dc.contributor.authorSimpson, M. A.en
dc.contributor.authorSreekantan-Nair, A.en
dc.contributor.authorPereira, A.en
dc.contributor.authorGünther, S.en
dc.contributor.authorJahic, A.en
dc.contributor.authorModarres, H.en
dc.contributor.authorMoore-Barton, H.en
dc.contributor.authorTrembath, R.C.en
dc.contributor.authorKabra, M.en
dc.contributor.authorBaple, E. L.en
dc.contributor.authorThakur, S.en
dc.contributor.authorPatton, M. A.en
dc.contributor.authorBeetz, C.en
dc.contributor.authorPawlak, R.en
dc.contributor.authorCrosby, Andrew H.en
dc.date.accessioned2016-08-24T08:29:30Z-
dc.date.available2016-08-24T08:29:30Z-
dc.date.issued2016-08-05-
dc.identifier.citationBrief Report: Novel Genetic, Clinical and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia. 2016 Nov;37(11):1157-1161 Hum. Mutat.en
dc.identifier.issn1098-1004-
dc.identifier.pmid27492651-
dc.identifier.doi10.1002/humu.23060-
dc.identifier.urihttp://hdl.handle.net/11287/618725-
dc.description.abstractHereditary 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. This article is protected by copyright. All rights reserved.en
dc.languageENG-
dc.language.isoenen
dc.publisherWileyen
dc.relation.urlhttp://dx.doi.org/10.1002/humu.23060en
dc.rightsArchived with thanks to Human Mutationen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleBrief Report: Novel Genetic, Clinical and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia.en
dc.typeJournal Articleen
dc.identifier.journalHuman Mutationen
dc.type.versionIn press (epub ahead of print)en

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