title: A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration.
abstract: The composition of the neuronal cell surface dictates synaptic plasticity and thereby cognitive development. This remodeling of the synapses is governed by the endocytic network which internalize transmembrane proteins, then sort them back to the cell surface or carry them to the lysosome for degradation. The multi-protein retromer complex is central to this selection, capturing specific transmembrane proteins and remodeling the cell membrane to form isolated cargo-enriched transport carriers. We investigated a consanguineous family with four patients who presented in infancy with intractable myoclonic epilepsy and lack of psychomotor development. Using exome analysis, we identified a homozygous deleterious mutation in SNX27, which encodes sorting nexin 27, a retromer cargo adaptor. In western analysis of patient fibroblasts, the encoded mutant protein was expressed at an undetectable level when compared with a control sample. The patients' presentation and clinical course recapitulate that reported for the SNX27 knock-out mouse. Since the cargo proteins for SNX27-mediated sorting include subunits of ionotropic glutamate receptors and endosome-to-cell surface synaptic insertion of AMPA receptors is severely perturbed in SNX27(-/-) neurons, it is proposed that at least part of the neurological aberrations observed in the patients is attributed to defective sorting of ionotropic glutamate receptors. SNX27 deficiency is now added to the growing list of neurodegenerative disorders associated with retromer dysfunction.
authors.affiliation: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors.forename: Nadirah
authors.initials: N
authors.lastname: Damseh
authors.affiliation: The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Danson
authors.affiliation: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors.forename: Motee
authors.initials: M
authors.lastname: Al-Ashhab
authors.affiliation: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors.forename: Bassam
authors.initials: B
authors.lastname: Abu-Libdeh
authors.affiliation: The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gallon
authors.affiliation: ReMemBr Group, Institute of Clinical Neurosciences, University of Bristol and North Bristol NHS Trust, Learning and Research Building, Southmead Hospital, Bristol BS10 5NB, UK.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center Jerusalem, Jerusalem, Israel.
authors.forename: Barak
authors.initials: B
authors.lastname: Yaacov
authors.affiliation: ReMemBr Group, Institute of Clinical Neurosciences, University of Bristol and North Bristol NHS Trust, Learning and Research Building, Southmead Hospital, Bristol BS10 5NB, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Coulthard
authors.affiliation: Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS1 3NY, UK.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Caldwell
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center Jerusalem, Jerusalem, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cullen
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center Jerusalem, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D001921:Brain / Q000473:pathology / Q000503:physiopathology; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010375:Pedigree; D058305:Sorting Nexins / Q000172:deficiency* / Q000235:genetics*
chemical_list: C522885:SNX27 protein, human; D058305:Sorting Nexins