SNX14-gene

SNX14 is the acronym for "SORTING NEXIN 14", a gene located on chromosome 6q14.3 that encodes a protein of the same name. Proteins containing an SNX-type phox homology (PX) domain, such as SNX14, are thought to be involved in endosome patterning. The SNX-type PX domain contains conserved arg-arg-tyr-X-asp/glu and pro-pro-X-pro-X-lys motifs (Bryant et al. 2018). In addition to the PX domain, SNX14 and other SNX RGS proteins also possess a Regulator of G-protein Signaling (RGS) domain, 2 hydrophobic N-terminal transmembrane helices, and PXA and PXC domains proximal to the N- and C-termini, respectively.

Carroll et al (2001) cloned Snx14 from mouse and rat. The derived rat protein contains 946 amino acids. Northern blot analyses of adult mouse tissue revealed a 4-kb transcript in the cerebellum and hippocampus, with lower expression in cortex, muscle, liver, lung, and heart. In situ hybridization of mouse embryos revealed predominant Snx14 expression in neuronal lineages, including ventricular region, floor plate, pituitary, eye, spinal cord, and inner ear. Snx14 was also expressed in the embryonic gut. Thomas et al. (2014) found ubiquitous expression of SNX14 in human fetal tissues, including heart, skin, brain, kidney, bone, liver, eye, and placenta. Akizu et al. (2015) found that SNX14 protein is localized in the late endosome/lysosomal compartment.

Mutations of the gene are associated with autosomal recessive "spinocerebellar ataxia 20," (OMIM: 616354).

By studying autosomal recessive cerebellar ataxia-20 fibroblasts taken from patients lacking SNX14 expression, Bryant et al. (2018) found that SNX14 has no direct role in regulating autolysosome formation. Loss of SNX14 had no effect on autophagosome-lysosome fusion. Autophagy remained intact in SNX14-deficient cells. Instead, morphological defects of the lysosomal compartments were found in SNX14-deficient cells. That is, loss of SNX14 leads to increased accumulation of autophagic organelles and disruption of intracellular cholesterol homeostasis. Furthermore, loss of SNX14 was shown to disrupt ER-associated neutral lipid metabolism. The fibroblasts of other patients showed cytoplasmic vacuoles with electron-dense material partly resembling lamellar corpuscles, suggesting a defect in the autophagy signaling pathway.

1. Akizu N et al (2015) Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction. Nature Genet 47: 528-534
2. Bryant D et al (2018) SNX14 mutations affect endoplasmic reticulum-associated neutral lipid metabolism in autosomal recessive spinocerebellar ataxia 20. Hum Molec Genet 27: 1927-1940.
3. Carroll P et al (2001) Sorting nexin-14, a gene expressed in motoneurons trapped by an in vitro preselection method. Dev Dyn 221: 431-442
4. Thomas AC et al (2015) Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome. Am J Hum Genet 96: 1008-1009