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. * Peter J. Cullen: Pete.Cullen@bristol.ac.uk. * Orly Elpeleg: Elpeleg@Hadassah.org.il. Ethical standards statement.The experiments comply with the current laws of Israel.

A human laterality disorder caused by a homozygous deleterious mutation inMMP21

“…Following alignment and variant calling, we performed a series of filtering steps. These included removing variants called less than X8, were off-target, heterozygous, synonymous, on the chromosome X, had minor allel frequency (MAF) >1% at ExAC (Exome Aggregation Consortium, Cambridge, Massachusetts, USA (URL: http://exac.broadinstitute.org)) and MAF >4% in the Hadassah in-house dbSNP 30. Thirteen variants survived this process (see online supplementary table S1), and we examined by Sanger sequencing those predicted to affect a residue with a high conservation score (Genomic Evolutionary Rate Profiling).…”

GPCR Signaling and Trafficking: The Long and Short of It

“…Insofar, all genetic mutations identified in SNX27 or retromer in humans have been linked to severe neuropathologies including Alzheimer’s disease [83], Parkinson’s disease [84, 85], Down syndrome [86] and infantile epilepsy [87] for recent reviews see [88, 89]. Accordingly, lowered expression of SNX27 or retromer reduces the surface cell levels of several cargo known to influence synaptic neurotransmission (N-methyl-D-aspartate receptors; NMDARs [90] and AMPARs[91], neuronal signaling and excitably (β 2 AR [90], GIRK2a [92] mGLuR5 [93]), glial cell differentiation (GPCR 17; GPR17 [94]) and, more recently, limiting the distribution of amyloid precursor protein (APP), a precursor linked to the onset and progression of Alzheimer’s disease [95].…”

Structural Insights into GIRK Channel Function

“…Both GIRK2c and GIRK3 channels have been shown to associate with sorting nexin 27 (SNX27) via a PDZ (PSD95/Disc large/Zona occludens) domain interaction (Lunn et al, 2007). SNX27 is a member of a large family of endosomal trafficking proteins (Cullen, 2008) and recently implicated in intractable myoclonic epilepsy (Damseh et al, 2015). GIRK2c and GIRK3 contain a C terminal class I PDZ-binding motif, E-S-K-V, that associates directly with the PDZ domain of SNX27.…”