title: Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis.
abstract: We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features. Exome sequencing identified one homozygous variant shared among all affected individuals and absent in controls: a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein. TECPR2 has been reported as a positive regulator of autophagy. We thus examined the autophagy-related fate of two key autophagic proteins, SQSTM1 (p62) and MAP1LC3B (LC3), in skin fibroblasts of an affected individual, as compared to a healthy control, and found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II). siRNA knockdown of TECPR2 showed similar changes, consistent with aberrant autophagy. Our results are strengthened by the fact that autophagy dysfunction has been implicated in a number of other neurodegenerative diseases. The discovered TECPR2 mutation implicates autophagy, a central intracellular mechanism, in spastic paraparesis.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. ozdanit@gmail.com
authors.forename: Danit
authors.initials: D
authors.lastname: Oz-Levi
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Ruzzo
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hitomi
authors.forename: Amir
authors.initials: A
authors.lastname: Gelman
authors.forename: Kimberly
authors.initials: K
authors.lastname: Pelak
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Haike
authors.initials: H
authors.lastname: Reznik-Wolf
authors.forename: Ifat
authors.initials: I
authors.lastname: Bar-Joseph
authors.forename: Tsviya
authors.initials: T
authors.lastname: Olender
authors.forename: Anna
authors.initials: A
authors.lastname: Alkelai
authors.forename: Meira
authors.initials: M
authors.lastname: Weiss
authors.forename: Edna
authors.initials: E
authors.lastname: Ben-Asher
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Zvulun
authors.initials: Z
authors.lastname: Elazar
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Elon
authors.initials: E
authors.lastname: Pras
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
mesh_terms: D001343:Autophagy / Q000235:genetics*; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007585:Jews / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D059906:Neuroimaging; D020336:Paraparesis, Spastic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C578280:TECPR2 protein, human