ausblenden:
Schlagwörter:
Adult
Age of Onset
Bone Diseases/etiology/*genetics/physiopathology
Cohort Studies
Cough/genetics/pathology/physiopathology
Endoplasmic Reticulum/*genetics/pathology
Exome/genetics
Female
Fractures, Bone/genetics/pathology
GTP Phosphohydrolases/*genetics
Gastroesophageal Reflux/genetics/pathology/physiopathology
Genes, Dominant/genetics
Haplotypes/genetics
Hereditary Sensory and Autonomic
Neuropathies/complications/*genetics/pathology/physiopathology
Humans
Intracellular Space/genetics
Male
Mutation
Mutation, Missense/genetics
Pedigree
Phenotype
Young Adult
Zusammenfassung:
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.
