Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Beetz C
,
Johnson A
,
Schuh AL
,
Thakur S
,
Varga RE
,
Fothergill T
,
Hertel N
,
Bomba-Warczak E
,
Thiele H
,
Nürnberg G
,
Altmüller J
,
Saxena R
,
Chapman ER
,
Dent EW
,
Nürnberg P
,
Audhya A
.
???displayArticle.abstract???
Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.
Abecasis,
GRR: graphical representation of relationship errors.
2001, Pubmed
Abecasis,
GRR: graphical representation of relationship errors.
2001,
Pubmed
Abecasis,
Merlin--rapid analysis of dense genetic maps using sparse gene flow trees.
2002,
Pubmed
Anderson,
Reshaping of the endoplasmic reticulum limits the rate for nuclear envelope formation.
2008,
Pubmed
Audhya,
A role for Rab5 in structuring the endoplasmic reticulum.
2007,
Pubmed
,
Xenbase
Auer-Grumbach,
Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.
2005,
Pubmed
Beetz,
Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.
2012,
Pubmed
Bian,
Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes.
2011,
Pubmed
Blackstone,
Hereditary spastic paraplegias: membrane traffic and the motor pathway.
2011,
Pubmed
Connell,
Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion.
2009,
Pubmed
Connerly,
Sec16 is a determinant of transitional ER organization.
2005,
Pubmed
Crisponi,
Crisponi syndrome is caused by mutations in the CRLF1 gene and is allelic to cold-induced sweating syndrome type 1.
2007,
Pubmed
Dykstra,
Yip1A structures the mammalian endoplasmic reticulum.
2010,
Pubmed
Edmonson,
Characterization of a human import component of the mitochondrial outer membrane, TOMM70A.
2002,
Pubmed
Fink,
Hereditary spastic paraplegia.
2006,
Pubmed
Friedman,
The ER in 3D: a multifunctional dynamic membrane network.
2011,
Pubmed
Greco,
Role of the TFG N-terminus and coiled-coil domain in the transforming activity of the thyroid TRK-T3 oncogene.
1998,
Pubmed
Greco,
The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain.
1995,
Pubmed
Gudbjartsson,
Allegro, a new computer program for multipoint linkage analysis.
2000,
Pubmed
Guelly,
Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.
2011,
Pubmed
Hazan,
Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia.
1999,
Pubmed
Hernández,
TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations.
1999,
Pubmed
Hertel,
Absence of layer-specific cadherin expression profiles in the neocortex of the reeler mutant mouse.
2011,
Pubmed
Hisaoka,
TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma.
2004,
Pubmed
Hu,
A class of dynamin-like GTPases involved in the generation of the tubular ER network.
2009,
Pubmed
Ikenaka,
Disruption of axonal transport in motor neuron diseases.
2012,
Pubmed
Ishiura,
The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement.
2012,
Pubmed
Ivanova,
Hereditary spastic paraplegia 3A associated with axonal neuropathy.
2007,
Pubmed
Kwong,
The role of mitochondria in inherited neurodegenerative diseases.
2006,
Pubmed
Lagier-Tourenne,
Rethinking ALS: the FUS about TDP-43.
2009,
Pubmed
Macedo-Souza,
Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13.
2005,
Pubmed
Maebayashi,
Expression and Localization of TRK-Fused Gene Products in the Rat Brain and Retina.
2012,
Pubmed
Mannan,
Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with Reticulon 1 an endoplasmic reticulum protein.
2006,
Pubmed
Montenegro,
Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12.
2012,
Pubmed
Newman,
Hereditary optic neuropathies: from the mitochondria to the optic nerve.
2005,
Pubmed
O'Connell,
PedCheck: a program for identification of genotype incompatibilities in linkage analysis.
1998,
Pubmed
Palmer,
The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery.
2011,
Pubmed
Park,
Further assembly required: construction and dynamics of the endoplasmic reticulum network.
2010,
Pubmed
Park,
Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network.
2010,
Pubmed
Pemberton,
Genomic patterns of homozygosity in worldwide human populations.
2012,
Pubmed
Rademakers,
Advances in understanding the molecular basis of frontotemporal dementia.
2012,
Pubmed
Renvoisé,
Emerging themes of ER organization in the development and maintenance of axons.
2010,
Pubmed
Rüschendorf,
ALOHOMORA: a tool for linkage analysis using 10K SNP array data.
2005,
Pubmed
Saada,
C6ORF66 is an assembly factor of mitochondrial complex I.
2008,
Pubmed
Saengsawang,
The F-BAR protein CIP4 inhibits neurite formation by producing lamellipodial protrusions.
2012,
Pubmed
Salinas,
Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms.
2008,
Pubmed
Schüle,
Genetics of hereditary spastic paraplegias.
2011,
Pubmed
Slavin,
Role of Rab1b in COPII dynamics and function.
2011,
Pubmed
Soderblom,
Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias.
2006,
Pubmed
Valenzuela,
Neuronal protein trafficking: emerging consequences of endoplasmic reticulum dynamics.
2011,
Pubmed
Viesselmann,
Nucleofection and primary culture of embryonic mouse hippocampal and cortical neurons.
2011,
Pubmed
Voeltz,
A class of membrane proteins shaping the tubular endoplasmic reticulum.
2006,
Pubmed
Voeltz,
Structural organization of the endoplasmic reticulum.
2002,
Pubmed
Watson,
Sec16 defines endoplasmic reticulum exit sites and is required for secretory cargo export in mammalian cells.
2006,
Pubmed
Witte,
TFG-1 function in protein secretion and oncogenesis.
2011,
Pubmed
Yoshida,
YIPF5 and YIF1A recycle between the ER and the Golgi apparatus and are involved in the maintenance of the Golgi structure.
2008,
Pubmed
Zanetti,
COPII and the regulation of protein sorting in mammals.
2011,
Pubmed
Zhao,
Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.
2001,
Pubmed
Zhu,
SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.
2006,
Pubmed
Züchner,
Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.
2006,
Pubmed
