Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.
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.
1 Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
Uwe
U
Kornak
Inès
I
Mademan
Marte
M
Schinke
Martin
M
Voigt
Peter
P
Krawitz
Jochen
J
Hecht
Florian
F
Barvencik
Thorsten
T
Schinke
Sebastian
S
Gießelmann
F Timo
FT
Beil
Adolf
A
Pou-Serradell
Juan J
JJ
Vílchez
Christian
C
Beetz
Tine
T
Deconinck
Vincent
V
Timmerman
Christoph
C
Kaether
Peter
P
De Jonghe
Christian A
CA
Hübner
Andreas
A
Gal
Michael
M
Amling
Stefan
S
Mundlos
Jonathan
J
Baets
Ingo
I
Kurth
D000328:Adult; D017668:Age of Onset; D001847:Bone Diseases / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D003371:Cough / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D050723:Fractures, Bone / Q000235:genetics / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005764:Gastroesophageal Reflux / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005799:Genes, Dominant / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D042541:Intracellular Space / Q000235:genetics; D008297:Male; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
D020558:GTP Phosphohydrolases; C529895:ATL3 protein, human
HSAN; axon; neurodegeneration; nociception; sensory neurons