6533b85ffe1ef96bd12c134e
RESEARCH PRODUCT
Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.
Sebastian GießelmannThorsten SchinkeInès MademanStefan MundlosStefan MundlosUwe KornakUwe KornakJuan J. VílchezJuan J. VílchezAndreas GalA. Pou-serradellTine DeconinckMichael AmlingPeter KrawitzMartin VoigtChristoph KaetherChristian A. HübnerMarte SchinkeVincent TimmermanChristian BeetzF. Timo BeilJonathan BaetsJochen HechtIngo KurthPeter De JongheFlorian Barvenciksubject
AtlastinAdultMaleIntracellular SpaceMutation MissenseSensory systemBiologymedicine.disease_causeEndoplasmic ReticulumGTP PhosphohydrolasesCohort StudiesFractures BoneYoung AdultmedicineMissense mutationHumansExomenociceptionAxonAge of OnsetHereditary Sensory and Autonomic NeuropathiesGenes DominantaxonGeneticsMutationEndoplasmic reticulumNeurodegenerationneurodegenerationmedicine.diseasePenetrancePedigreeHSANsensory neuronsmedicine.anatomical_structurePhenotypeCoughHaplotypesMutationGastroesophageal RefluxFemaleNeurology (clinical)Human medicineBone DiseasesNeurosciencedescription
Many neurodegenerative disorders present with sensory loss. In the group of hereditary sensory and autonomic neuropathies loss of nociception is one of the disease hallmarks. To determine underlying factors of sensory neurodegeneration we performed whole-exome sequencing in affected individuals with the disorder. In a family with sensory neuropathy with loss of pain perception and destruction of the pedal skeleton we report a missense mutation in a highly conserved amino acid residue of atlastin GTPase 3 (ATL3), an endoplasmic reticulum-shaping GTPase. The same mutation (p.Tyr192Cys) was identified in a second family with similar clinical outcome by screening a large cohort of 115 patients with hereditary sensory and autonomic neuropathies. Both families show an autosomal dominant pattern of inheritance and the mutation segregates with complete penetrance. ATL3 is a paralogue of ATL1, a membrane curvature-generating molecule that is involved in spastic paraplegia and hereditary sensory neuropathy. ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network. Mutant ATL3 p.Tyr192Cys fails to localize to branch points, but instead disrupts the structure of the tubular endoplasmic reticulum, suggesting that the mutation exerts a dominant-negative effect. Identification of ATL3 as novel disease-associated gene exemplifies that long-term sensory neuronal maintenance critically depends on the structural organisation of the endoplasmic reticulum. It emphasizes that alterations in membrane shaping-proteins are one of the major emerging pathways in axonal degeneration and suggests that this group of molecules should be considered in neuroprotective strategies. * Abbreviations : HSAN : hereditary sensory and autonomic neuropathies PDI : protein disulphide isomerase SPG : spastic paraplegia
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-01-01 | Brain : a journal of neurology |