Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

Abstract

Pediatric-onset ataxias often present clinically with developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a novel clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in sorting nexin 14 (SNX14), encoding a ubiquitously expressed modular PX-domain-containing sorting factor. We found SNX14 localized to lysosomes, and associated with phosphatidyl-inositol (3,5)P2, a key component of late endosomes/lysosomes. Patient cells showed engorged lysosomes and slower autophagosome clearance rate upon starvation induction. Zebrafish morphants showed dramatic loss of cerebellar parenchyma, accumulated autophagosomes, and activation of apoptosis. Our results suggest a unique ataxia syndrome due to biallelic SNX14 mutations, leading to lysosome-autophagosome dysfunction.

Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans

“…8h-s). Next, we undertook histological analysis of P0 cortical sections stained with sera against LC3 and p62, which serves a cargo receptor for the autophagic degradation of ubiquitinated substrates 26 . We observed a large increase in the number of cells with p62+ (Fig.…”

“…More recently, mutations in SNX14, a protein that is associated with late endosomes and lysosomes and that binds to phosphatidylinositol (3,5)-bisphosphate, was shown to cause cerebellar atrophy. This phenotype was associated with impaired autophagic clearance and subsequent caspase-induced cell death 26 . This work suggests that mutations in the VPS15–VPS34–BECLIN1 complex may be associated with neurological disorders, both common and rare.…”

“…Antibodies targeting phosphoproteins were incubated with 1 mM sodium orthovanadate in 0.5% BSA/TBS. The following primary antibodies were used: 1:2,000 Vps15 for mouse studies (Novus Biologicals NBP1-30463) 39 , 1:1,000 VPS15 for human studies (Abcam ab124817, Abcam ab128903) 41 , 1:500 Vps34 (Cell Signaling, #3811) 42,43 , 1:1,000 Beclin1 (Cell Signaling #3738) 44 , 1:500 p62 (Novus Biologicals, H00008878-M01) 45 , 1:2,000 GAPDH (Millipore, MAB3 74) 26,46 , 1:1,000 ubiquitin (Santa Cruz, sc-8017) 47 , 1:10,000 α-tubulin (Sigma Aldrich, T6199) 48 , 1:100 LC3 (Nanotools, 0260-100/LC3-2G6) 49 , 1:600 EGFR (Cell Signaling #4267 S) 50 , 1:200 Nischarin (Santa Cruz, sc-365364) 21 , 1:500 PAK1 T423 (Cell Signaling, #2601 S) 51 and 1:500 N -terminal Vps15 antibody (Proteintech, 17894-1-AP). Western blots were quantified using ImageJ.…”

Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease

“…The SNX14 gene, homozygously deleted almost in its entirety in BAB3498 and harboring a homozygous frameshift insertion in patient CGD-62463468, encodes a protein of the sorting nexin family, important in cell trafficking and signaling (Mas et al, 2014). While our work was in progress another group independently reported SNV mutations of this gene in association with intellectual disability, coarse face and hypoplasia of the cerebellum, specifically without microcephaly (Akizu et al, 2015; Thomas et al, 2014). The microcephaly observed in BAB3498 may reflect a more severe phenotype associated with the larger homozygous deletion or possibly a yet unidentified modifier gene.…”

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

“…Mutations in the autophagy gene WDR45 have been associated with static encephalopathy of childhood with generation in adulthood (SENDA), and SENDA disease phenotypes (iron accumulation and cerebral atrophy) appear to be restricted to the brain despite WDR45 expression in skeletal muscle (7). Brain-related disease phenotypes have also been observed in patients with a form of hereditary spastic paraparesis bearing a recessive mutation in the putative autophagy regulator TECPR2, and in patients suffering from cerebellar atrophy associated with mutations in the autophagy modulator SNX14 (8,9).…”