Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures, and ataxia. We exome-sequenced 84 unrelated PME patients of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation c.959G>A (p.Arg320His) in KCNC1 was identified as a novel major cause for PME. Eleven unrelated exome-sequenced (13%) and two patients in a secondary cohort (7%) had this mutation. KCNC1 encodes K V 3.1, a subunit of the K V 3 voltage-gated K + channels, major determinants of high-frequency neuronal firing. Functional analysis of the p.Arg320His mutant channel revealed a dominant-negative loss-of-function effect. Ten patients had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6, SERPINI1). Identification of mutations in PRNP, SACS, and TBC1D24 expand their phenotypic spectrum to PME. These findings provide important insights into the molecular genetic basis of PME and reveal the role of de novo mutations in this disease entity.Correspondence should be addressed to Anna-Elina Lehesjoki (anna-elina.lehesjoki@helsinki.fi). Author Contributions Accession codesMutation nomenclatures correspond to the following canonical Ensembl transcripts: KCNC1, ENST00000265969.6; NEU1, ENST00000375631.4; NHLRC1, ENST00000340650.3; EPM2A, ENST00000367519.3; CLN6, ENST00000249806.5; AFG3L2, ENST00000269143.3; TBC1D24, ENST00000293970.5; SACS, ENST00000382298.3; SERPINI1, ENST00000295777.5; PRNP, ENST00000379440.4; SCN1A, ENST00000303395.4. The raw aligned sequence reads were submitted to the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home) by Wellcome Trust Sanger Institute under study accession numbers EGAS00001000048 and EGAS00001000386. Competing Financial InterestsAuthors declare no potential competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2015 July 01. Published in final edited form as:Nat Genet. 5,6 and GOSR2 7 also contribute to cases of PME with preserved cognition. Other PMEs may have additional features, particularly dementia. PME-associated genes encode a variety of proteins, many of them being associated with endosomal and lysosomal function 8,9 , but the associated disease mechanisms are generally poorly understood.The precise clinical diagnosis of specific forms of PME is challenging due to their genetic heterogeneity, phenotypic similarities and overlap of symptoms with other epileptic and neurodegenerative diseases. In many cases, there are no distinguishing clinical features or biomarkers. Consequently, a substantial proportion of PME cases remain without a molecular diagnosis 3 .Here, we aimed to identify the causative genes for unsolved PME cases by employing exome sequencing in unrelated patients assembled from multiple centers in Europe, North America, Asia, and Australia over a 25-year period. The extent of previous molecular studies varied, but all cases were negative for mutations in the ...

Recessive splice site and nonsense mutations of PCDH15, encoding protocadherin 15, are known to cause deafness and retinitis pigmentosa in Usher syndrome type 1F (USH1F). Here we report that non-syndromic recessive hearing loss (DFNB23) is caused by missense mutations of PCDH15. This suggests a genotype-phenotype correlation in which hypomorphic alleles cause non-syndromic hearing loss, while more severe mutations of this gene result in USH1F. We localized protocadherin 15 to inner ear hair cell stereocilia, and to retinal photoreceptors by immunocytochemistry. Our results further strengthen the importance of protocadherin 15 in the morphogenesis and cohesion of stereocilia bundles and retinal photoreceptor cell maintenance or function.

Dopamine transporter deficiency syndrome is an SLC6A3-related progressive infantile-onset parkinsonism-dystonia that mimics cerebral palsy. Ng et al. describe clinical features and molecular findings in a new cohort of patients. They report infants with classical disease, as well as young adults manifesting as atypical juvenile-onset parkinsonism-dystonia, thereby expanding the disease spectrum.

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BackgroundAcinetobacter baumannii has emerged as a significant nosocomial pathogen during the last few years, exhibiting resistance to almost all major classes of antibiotics. Alternative treatment options such as vaccines tend to be most promising and cost effective approaches against this resistant pathogen. In the current study, we have explored the pan-genome of A. baumannii followed by immune-proteomics and reverse vaccinology approaches to identify potential core vaccine targets.ResultsThe pan-genome of all available A. baumannii strains (30 complete genomes) is estimated to contain 7,606 gene families and the core genome consists of 2,445 gene families (~32 % of the pan-genome). Phylogenetic tree, comparative genomic and proteomic analysis revealed both intra- and inter genomic similarities and evolutionary relationships. Among the conserved core genome, thirteen proteins, including P pilus assembly protein, pili assembly chaperone, AdeK, PonA, OmpA, general secretion pathway protein D, FhuE receptor, Type VI secretion system OmpA/MotB, TonB dependent siderophore receptor, general secretion pathway protein D, outer membrane protein, peptidoglycan associated lipoprotein and peptidyl-prolyl cis-trans isomerase are identified as highly antigenic. Epitope mapping of the target proteins revealed the presence of antigenic surface exposed 9-mer T-cell epitopes. Protein-protein interaction and functional annotation have shown their involvement in significant biological and molecular processes. The pipeline is validated by predicting already known immunogenic targets against Gram negative pathogen Helicobacter pylori as a positive control.ConclusionThe study, based upon combinatorial approach of pan-genomics, core genomics, proteomics and reverse vaccinology led us to find out potential vaccine candidates against A. baumannii. The comprehensive analysis of all the completely sequenced genomes revealed thirteen putative antigens which could elicit substantial immune response. The integration of computational vaccinology strategies would facilitate in tackling the rapid dissemination of resistant A.baumannii strains. The scarcity of effective antibiotics and the global expansion of sequencing data making this approach desirable in the development of effective vaccines against A. baumannii and other bacterial pathogens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2951-4) contains supplementary material, which is available to authorized users.