PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins.

During neurotransmission, synaptic vesicles undergo multiple rounds of exo-endocytosis, involving recycling and/or degradation of synaptic proteins. While ubiquitin signaling at synapses is essential for neural function, it has been assumed that synaptic proteostasis requires the ubiquitin-proteasome system (UPS). We demonstrate here that turnover of synaptic membrane proteins via the endolysosomal pathway is essential for synaptic function. In both human and mouse, hypomorphic mutations in the ubiquitin adaptor protein PLAA cause an infantile-lethal neurodysfunction syndrome with seizures. Resulting from perturbed endolysosomal degradation, Plaa mutant neurons accumulate K63-polyubiquitylated proteins and synaptic membrane proteins, disrupting synaptic vesicle recycling and neurotransmission. Through characterization of this neurological intracellular trafficking disorder, we establish the importance of ubiquitin-mediated endolysosomal trafficking at the synapse.This work was supported by core funding from the MRC (MC_UU_12018/26 to E.A.H., G.R.M., and P.M.; MC_PC_U127527200 to P.B., M.A.K., L.M., R.L.M., and I.J.J.; and MC_UU_12016/6 to Y. Kulathu and Y. Kristaryanto), MRCMICA grant (to M.S.N.), Muscular Dystrophy Association (MDA294433) (to L.M.M.), Science Foundation Ireland (13/SIRG/2174) (to A.G.-M. and A.v.K.), NIHR Cambridge BRC 2012 (to C.G.W.), MRC, Wellcome, and WellChild (to E.R.M.), and King Salman Center for Disability Research (to F.S.A.)

Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.

BACKGROUND Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant multisystem disorder with skin (fibrofolliculomas or trichodiscomas), lung (cysts and pneumothorax) and kidney (renal cell carcinoma) tumours. Although colorectal neoplasia was reported initially to be part of the BHD phenotype, some recent studies have not confirmed this association. METHODS A series of clinical and laboratory studies was undertaken to investigate possible relationships between colorectal neoplasia and the BHD gene (FLCN). The studies investigated whether individuals with familial colorectal cancer of unknown cause might have unsuspected germline FLCN mutations, looked for somatic FLCN C(8) tract mutations in microsatellite unstable sporadic colorectal cancers, and assessed the risk of colorectal neoplasia and possible genotype-phenotype correlations in BHD patients. RESULTS Although it was found previously that germline FLCN mutations can be detected in approximately 5% of patients with familial renal cell carcinoma, germline FLCN mutations were not detected in 50 patients with familial non-syndromic colorectal cancer. Analysis of genotype-phenotype correlations for two recurrent FLCN mutations identified in a subset of 51 families with BHD demonstrated a significantly higher risk of colorectal neoplasia in c.1285dupC mutation (within the exon 11 C(8) mononucleotide tract) carriers than in c.610delGCinsTA mutation carriers (chi(2)=5.78, p=0.016). Somatic frameshift mutations in the FLCN exon 11 C(8) mononucleotide tract were detected in 23% of sporadic colorectal cancers with microsatellite instability, suggesting that FLCN inactivation might contribute to colorectal tumourigenesis. CONCLUSIONS These findings suggest that the previously reported clinical heterogeneity for colorectal neoplasia may reflect allelic heterogeneity and the risk of colorectal neoplasia in BHD syndrome requires further investigation

ModFetch: A modular system for automating queries to relational databases

Computer Science