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Sapna Khowal, Samar Husain Naqvi, Seema Monga, Swatantra Kumar Jain, Saima Wajid
The intriguing molecular pathways involved in oral carcinogenesis are still ambiguous. The oral squamous cell carcinoma (OSCC) ranks as the most common type constituting more than 90% of the globally diagnosed oral cancers cases. The elevation in the OSCC incidence rate during past ten years has an alarming impression on human healthcare. The major challenges associated with OSCC include delayed diagnosis, high metastatic rates, and low five-year survival rates. The present work foundations on reverse genetic strategy and involves the identification of genes showing expressional variability in an OSCC case lacking addictive proclivities for tobacco, betel nut and/or alcohol, major etiologies...
December 13, 2017: Journal of Cellular Biochemistry
Susanne A Schneider, Roy N Alcalay
Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi-allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3)...
November 2017: Movement Disorders: Official Journal of the Movement Disorder Society
Andreas Puschmann
PURPOSE OF REVIEW: This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes. RECENT FINDINGS: Newly reported genes for dominant Parkinson's disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted...
September 2017: Current Neurology and Neuroscience Reports
Erica L Gorenberg, Sreeganga S Chandra
Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions...
2017: Frontiers in Neuroscience
Jay P Ross, Nicolas Dupre, Yves Dauvilliers, Stephanie Strong, Amirthagowri Ambalavanan, Dan Spiegelman, Alexandre Dionne-Laporte, Emanuelle Pourcher, Melanie Langlois, Michel Boivin, Claire S Leblond, Patrick A Dion, Guy A Rouleau, Ziv Gan-Or
DNAJC13 mutations have been suggested to cause Parkinson's disease (PD), yet subsequent studies reported conflicting results on this association. In the present study, we sequenced the coding region of DNAJC13 in a French-Canadian/French cohort of 528 PD patients and 692 controls. A total of 62 (11.7%) carriers of rare DNAJC13 variants were identified among the PD patients compared with 82 (11.8%) among controls (p = 1.0). Two variants that were previously suggested to be associated with PD, p.R1516H and p...
September 2016: Neurobiology of Aging
Fernando Cardona, Jordi Perez-Tur
In order to explain the molecular causes of Parkinson's Disease (PD) it is important to understand the effect that mutations described as causative of the disease have at the functional level. In this special issue, several authors have been reviewing the effects in PD and other parkinsonisms of mutations described in LRRK2, α-synuclein, PINK1-Parkin-DJ-1, UCHL1, ATP13A2, GBA, VPS35, FBOX7 and HTRA2. In this review, we compile the knowledge about other proteins with a more general role in neurodegenerative diseases (MAPT) or for which less data is available due to its recent discovery (EIF4G1, DNAJC13), the lack of structural or functional data (as for PLA2G6 or DNAJC6), or even their doubtful association with the disease (as for GIGYF2, SYNJ1 and SPR)...
2017: Current Protein & Peptide Science
O Lorenzo-Betancor, K Ogaki, A I Soto-Ortolaza, C Labbe, R L Walton, A J Strongosky, J A van Gerpen, R J Uitti, P J McLean, W Springer, J Siuda, G Opala, A Krygowska-Wajs, M Barcikowska, K Czyzewski, A McCarthy, T Lynch, A Puschmann, I Rektorova, Y Sanotsky, C Vilariño-Güell, M J Farrer, T J Ferman, B F Boeve, R C Petersen, J E Parisi, N R Graff-Radford, D W Dickson, Z K Wszolek, O A Ross
BACKGROUND: Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. METHODS: In the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). RESULTS: Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13...
September 2015: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Rebecca M Perrett, Zoi Alexopoulou, George K Tofaris
Parkinson's disease is primarily a movement disorder with predilection for the nigral dopaminergic neurons and is often associated with widespread neurodegeneration and diffuse Lewy body deposition. Recent advances in molecular genetics and studies in model organisms have transformed our understanding of Parkinson's pathogenesis and suggested unifying biochemical pathways despite the clinical heterogeneity of the disease. In this review, we summarized the evidence that a number of Parkinson's associated genetic mutations or polymorphisms (LRRK2, VPS35, GBA, ATP13A2, ATP6AP2, DNAJC13/RME-8, RAB7L1, GAK) disrupt protein trafficking and degradation via the endosomal pathway and discussed how such defects could arise from or contribute to the accumulation and misfolding of α-synuclein in Lewy bodies...
May 2015: Molecular and Cellular Neurosciences
Zhaoying Yang, Miao He, Keren Wang, Guang Sun, Lu Tang, Zheli Xu
Breast cancer is still a leading cause of cancer deaths in women. Despite improvements in therapeutic approaches in local control, metastatic relapse is almost always incurable, underlining the importance to better understand the biological bases that contribute to disease progression. In this study, we demonstrated that miR-193b was significantly down-regulated in two primary human breast cancer cell lines (MDA-MB-231 and MCF-7). Reconstitution of miR-193b expression resulted in decreasing cell proliferation, clonogenicity, migration and invasion...
2014: International Journal of Clinical and Experimental Pathology
Emil K Gustavsson, Joanne Trinh, Ilaria Guella, Carles Vilariño-Güell, Silke Appel-Cresswell, A Jon Stoessl, Joseph K Tsui, Martin McKeown, Alex Rajput, Ali H Rajput, Jan O Aasly, Matthew J Farrer
BACKGROUND: A novel mutation (p.N855S) in DNAJC13 has been linked to familial, late-onset Lewy body parkinsonism in a Dutch-German-Russian Mennonite multi-incident kindred. METHODS: DNAJC13 was sequenced in 201 patients with parkinsonism and 194 controls from Canada. Rare (minor allele frequency < 0.01) missense variants identified in patients were genotyped in two Parkinson's disease case-controls cohorts. RESULTS: Eighteen rare missense mutations were identified; four were observed in controls, three were observed in both patients and controls, and eleven were identified only in patients...
February 2015: Movement Disorders: Official Journal of the Movement Disorder Society
Joanne Trinh, Ilaria Guella, Matthew James Farrer
IMPORTANCE: Mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 have been implicated in late-onset familial parkinsonism. However, the estimated disease penetrance of these mutations varies widely. OBJECTIVE: To compare penetrance of various mutations reported in published genetic studies to improve the understanding of late-onset parkinsonism. DATA SOURCES: Forty-nine previously published studies, including 709 participants, were included for all original and subsequent articles in ISI Web of Science, PubMed electronic databases, and extracted information about number of mutation carriers within families and sporadic cases worldwide for pathogenic mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13...
December 2014: JAMA Neurology
Silke Appel-Cresswell, Ali H Rajput, Vesna Sossi, Christina Thompson, Vanessa Silva, Jessamyn McKenzie, Katherine Dinelle, Siobhan E McCormick, Carles Vilariño-Güell, A Jon Stoessl, Dennis W Dickson, Chris A Robinson, Matthew J Farrer, Alex Rajput
BACKGROUND: Families of Dutch-German-Russian Mennonite descent with multi-incident parkinsonism have been identified as harboring a pathogenic DNAJC13 p.N855S mutation and are awaiting clinical and pathophysiological characterization. METHODS: Family members were examined clinically longitudinally, and 5 underwent dopaminergic PET imaging. Four family members came to autopsy. RESULTS: Of the 16 symptomatic DNAJC13 mutation carriers, 12 had clinically definite, 3 probable, and 1 possible Parkinson's disease (PD)...
November 2014: Movement Disorders: Official Journal of the Movement Disorder Society
Alex Rajput, Jay P Ross, Cecily Q Bernales, Sruti Rayaprolu, Alexandra I Soto-Ortolaza, Owen A Ross, Jay van Gerpen, Ryan J Uitti, Zbigniew K Wszolek, Ali H Rajput, Carles Vilariño-Güell
Exome-sequencing analyses have identified vacuolar protein sorting 35 homolog (VPS35) and DnaJ (Hsp40) homolog, subfamily C, member 13 (DNAJC13) harboring disease-causing variants for Parkinson disease (PD). Owing to the suggested clinical, pathological and genetic overlap between PD and essential tremor (ET) we assessed the presence of two VPS35 and DNAJC13 disease-causing variants in ET patients. TaqMan probes were used to genotype VPS35 c.1858G>A (p.(D620N)) (rs188286943) and DNAJC13 c.2564A>G (p.(N855S)) (rs387907571) in 571 ET patients of European descent, and microsatellite markers were used to define the disease haplotype in variant carriers...
June 2015: European Journal of Human Genetics: EJHG
Matthew Nj Seaman, Caroline L Freeman
The retromer complex mediates endosomal protein sorting by concentrating membrane proteins (cargo) into nascent tubules formed through the action of sorting nexin (SNX) proteins. The WASH complex is recruited to endosomes by binding to the VPS35 subunit of retromer and facilitates cargo protein sorting by promoting formation of endosomally-localized F-actin. The VPS35 protein is mutated in Parkinson disease (PD) and a recent report has revealed that the PD-causing mutation impairs the association of retromer with the WASH complex leading to perturbed endosomal protein sorting...
2014: Communicative & Integrative Biology
Carles Vilariño-Güell, Alex Rajput, Austen J Milnerwood, Brinda Shah, Chelsea Szu-Tu, Joanne Trinh, Irene Yu, Mary Encarnacion, Lise N Munsie, Lucia Tapia, Emil K Gustavsson, Patrick Chou, Igor Tatarnikov, Daniel M Evans, Frederick T Pishotta, Mattia Volta, Dayne Beccano-Kelly, Christina Thompson, Michelle K Lin, Holly E Sherman, Heather J Han, Bruce L Guenther, Wyeth W Wasserman, Virginie Bernard, Colin J Ross, Silke Appel-Cresswell, A Jon Stoessl, Christopher A Robinson, Dennis W Dickson, Owen A Ross, Zbigniew K Wszolek, Jan O Aasly, Ruey-Meei Wu, Faycal Hentati, Rachel A Gibson, Peter S McPherson, Martine Girard, Michele Rajput, Ali H Rajput, Matthew J Farrer
A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA...
April 1, 2014: Human Molecular Genetics
Jia Nee Foo, Herty Liany, Louis C Tan, Wing-Lok Au, Kumar-M Prakash, Jianjun Liu, Eng-King Tan
Mutations in DNAJC13, DNAJC6 and DNAJC5 have been implicated in Parkinson's disease (PD). To determine if rare coding variants in these genes play a role in PD risk in the Chinese population, we sequenced all coding exons of the three genes in 99 early-onset PD cases and 99 controls, and genotyped 8 missense variants in another 711 PD cases and 539 controls. Besides two common missense variants that did not show association with PD, the remaining missense variants were extremely rare (<0.5%), found in healthy population controls and did not show enrichment in PD cases...
April 2014: Neurobiology of Aging
Yi Guo, Xiong Deng, Jie Zhang, Linyan Su, Hongbo Xu, Ziqiang Luo, Hao Deng
Tourette syndrome/chronic tic phenotype (TS-CTD) is a neurological disorder manifested particularly by motor and vocal tics and associated with a variety of behavioral abnormalities. Recently, the mitochondrial ribosomal protein L3 gene (MRPL3) S75N, the DnaJ (Hsp40) homolog subfamily C member 13 gene (DNAJC13) A2057S, the orofacial cleft 1 candidate 1 gene (OFCC1) R129G and c.-5A>G variants are reported to be associated with Tourette syndrome/chronic tic phenotype (TS-CTD) in patients of European ancestry...
May 23, 2012: Neuroscience Letters
Senthil K Sundaram, Ahm M Huq, Zhen Sun, Wu Yu, Lindsey Bennett, Benjamin J Wilson, Michael E Behen, Harry T Chugani
Ten members of a 3-generation pedigree with 7 showing Tourette syndrome/chronic tic phenotype (TS-CTD) were evaluated with whole exome sequencing. We identified 3 novel, nonsynonymous single nucleotide variants in the MRPL3, DNAJC13, and OFCC1 genes that segregated with chronic tic phenotype. These variants were not present in 100 control subjects or in dbSNP/1000 Genomes databases. A novel variant in the 5' untranslated region of the OFCC1 gene was found in 2 TS-CTD patients from a different pedigree. Further studies will clarify the importance of variants in MRPL3, DNAJC13, and OFCC1 genes in TS...
May 2011: Annals of Neurology
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