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Eduardo Calpena, Víctor López Del Amo, Mouli Chakraborty, Beatriz Llamusí, Rubén Artero, Carmen Espinós, Máximo I Galindo
Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells, with crucial implications for human pathophysiology. In mammals, this family consists of four members (JPH1-JPH4) that are differentially expressed throughout excitable cells. The analysis of knockout mice lacking JPH subtypes has demonstrated their essential contribution to physiological functions in skeletal and cardiac muscles and in neurons. Moreover, mutations in the human JPH2 gene are associated with hypertrophic and dilated cardiomyopathies; mutations in JPH3 are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas JPH1 acts as a genetic modifier in Charcot-Marie-Tooth 2K peripheral neuropathy...
January 17, 2018: Disease Models & Mechanisms
C Ocampo, R Daimari, A A Oyekunle
Huntington's disease-like 2 (HDL2) is a rare autosomal dominant progressive neurodegenerative disorder commonly seen in adults. It was first described in a large African-American family in the United States. HDL2 clinically resembles Huntington's disease (HD) and causes adult-onset relentlessly progressive movement, emotional and cognitive dysfunction. Onset is usually in the fourth decade with slow progression to death. We present a 47-year-old male Botswana native, with a four-year-history of chorea, slurred speech, mood instability, cognitive impairment and weight loss...
January 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Xiaotong Hu, Yeye Kuang, Lili Li, Haimei Tang, Qinglan Shi, Xingsheng Shu, Yanjiao Zhang, Francis Kl Chan, Qian Tao, Chao He
Junctophilin (JPH) proteins stabilize junctional membrane complexes between plasma membrane and endoplasmic reticulum, also implicated in some human diseases. JPH3 mutations are linked to Huntington's disease-like 2 syndrome. Through epigenomic study of a colon cancer cell line pair (HCT116 and DKO), we identified JPH3 as a methylated novel tumor suppressor gene (TSG) candidate at 16q24. We further studied its epigenetic alterations and functions in digestive tumorigenesis. JPH3 expression at the RNA level was found to be frequently silenced or reduced in colorectal and gastric cancers due to its promoter CpG methylation, which is associated with tumor progression and poor survival of digestive cancer patients...
2017: Theranostics
Alejandro Romero, Eva Ramos, Irma Ares, Víctor Castellano, Marta Martínez, María-Rosa Martínez-Larrañaga, Arturo Anadón, María-Aránzazu Martínez
In this study, we investigated the induction of oxidative stress and apoptosis in human neuroblastoma cell line SH-SY5Y in response to alpha-cypermethrin (α-CYPER) exposure. MTT and LDH assays were carried out to assess the α-CYPER cytotoxicity. The IC50 value for α-CYPER was calculated to be 78.3 ± 2.98 µM for the MTT assay and 71.5 ± 3.94 µM for LDH assay. The pyrethroid α-CYPER (1-100 µM), in a dose-dependent manner, induced a significant increase in lipid peroxides measured as malondialdehyde (MDA) and in the levels of nitric oxide (NO)...
May 2017: Archives of Toxicology
Louise-Laure Mariani, Christelle Tesson, Perrine Charles, Cécile Cazeneuve, Valérie Hahn, Katia Youssov, Leorah Freeman, David Grabli, Emmanuel Roze, Sandrine Noël, Jean-Noel Peuvion, Anne-Catherine Bachoud-Levi, Alexis Brice, Giovanni Stevanin, Alexandra Durr
IMPORTANCE: Huntington disease (HD), a prototypic monogenic disease, is caused by an expanded CAG repeat in the HTT gene exceeding 35 units. However, not all patients with an HD phenotype carry the pathological expansion in HTT, and the positive diagnosis rate is poor. OBJECTIVES: To examine patients with HD phenotypes to determine the frequency of HD phenocopies with typical features of HD but without pathological CAG repeat expansions in HTT in an attempt to improve the positive diagnosis rate...
September 1, 2016: JAMA Neurology
L Li, Z-F Pan, X Huang, B-W Wu, T Li, M-X Kang, R-S Ge, X-Y Hu, Y-H Zhang, L-J Ge, D-Y Zhu, Y-L Wu, Y-J Lou
It is well accepted that junctophilin (JPHs) isoforms act as a physical bridge linking plasma membrane and endoplasmic reticulum (ER) for channel crosstalk in excitable cells. Our purpose is to investigate whether JPHs are involved in the proper communication between Ca(2+) influx and subsequent Ca(2+) amplification in pancreatic beta cells, thereby participating in regulating insulin secretion. The expression of JPH isoforms was examined in human and mouse pancreatic tissues, and JPH3 expression was found in both the beta cells...
June 23, 2016: Cell Death & Disease
Xiaoxi Liu, Takafumi Shimada, Takeshi Otowa, Yu-Yu Wu, Yoshiya Kawamura, Mamoru Tochigi, Yasuhide Iwata, Tadashi Umekage, Tomoko Toyota, Motoko Maekawa, Yoshimi Iwayama, Katsuaki Suzuki, Chihiro Kakiuchi, Hitoshi Kuwabara, Yukiko Kano, Hisami Nishida, Toshiro Sugiyama, Nobumasa Kato, Chia-Hsiang Chen, Norio Mori, Kazuo Yamada, Takeo Yoshikawa, Kiyoto Kasai, Katsushi Tokunaga, Tsukasa Sasaki, Susan Shur-Fen Gau
Autism spectrum disorder is a heterogeneous neurodevelopmental disorder with strong genetic basis. To identify common genetic variations conferring the risk of ASD, we performed a two-stage genome-wide association study using ASD family and healthy control samples obtained from East Asian populations. A total of 166 ASD families (n = 500) and 642 healthy controls from the Japanese population were used as the discovery cohort. Approximately 900,000 single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genome-Wide Human SNP array 6...
March 2016: Autism Research: Official Journal of the International Society for Autism Research
Hyeonsoo Jeong, Ki-Duk Song, Minseok Seo, Kelsey Caetano-Anollés, Jaemin Kim, Woori Kwak, Jae-Don Oh, EuiSoo Kim, Dong Kee Jeong, Seoae Cho, Heebal Kim, Hak-Kyo Lee
BACKGROUND: Natural and artificial selection following domestication has led to the existence of more than a hundred pig breeds, as well as incredible variation in phenotypic traits. Berkshire pigs are regarded as having superior meat quality compared to other breeds. As the meat production industry seeks selective breeding approaches to improve profitable traits such as meat quality, information about genetic determinants of these traits is in high demand. However, most of the studies have been performed using trained sensory panel analysis without investigating the underlying genetic factors...
2015: BMC Genetics
Amanda Krause, Claire Mitchell, Fahmida Essop, Susan Tager, James Temlett, Giovanni Stevanin, Christopher Ross, Dobrila Rudnicki, Russell Margolis
Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation...
October 2015: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Elizabeth Ann Coleman, Jeannette Y Lee, Stephen W Erickson, Julia A Goodwin, Naveen Sanathkumar, Vinay R Raj, Daohong Zhou, Kent D McKelvey, Senu Apewokin, Owen Stephens, Carol A Enderlin, Annette Juul Vangsted, Patty J Reed, Elias J Anaissie
PURPOSE: High-dose chemotherapy and autologous stem cell transplant (ASCT) to treat multiple myeloma (MM) and other cancers carries the risk of oral mucositis (OM) with sequelae including impaired nutritional and fluid intake, pain, and infectious complications. As a result of these problems, cancer treatment may have to be interrupted or delayed. In this study, we looked beyond OM's known risk factors of renal function and melphalan dose with a genome-wide association study (GWAS) to evaluate whether genetic variants in conjunction with clinical risk factors influence predisposition for OM...
March 2015: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Andrea H Seeley, Mark A Durham, Mark A Micale, Jeffrey Wesolowski, Bradley R Foerster, Donna M Martin
Macrocerebellum is a rare condition characterized by enlargement of the cerebellum with conservation of the overall shape and cytoarchitecture. Here, we report on a child with a distinctive constellation of clinical features including macrocerebellum, epilepsy, apparent intellectual disability, dysautonomia, gut malrotation, and poor gut motility. Oligonucleotide chromosome microarray analysis identified a 16q24.1-q24.2 deletion that included four OMIM genes (FBXO31, MAP1LC3B, JPH3, and SLC7A5). Review of prior studies describing individuals with similar or overlapping16q24...
August 2014: American Journal of Medical Genetics. Part A
Matthew D Figley, Anna Thomas, Aaron D Gitler
Intermediate-length polyglutamine expansions in ataxin 2 are a risk factor for amyotrophic lateral sclerosis (ALS). The polyglutamine tract is encoded by a trinucleotide repeat in a coding region of the ataxin 2 gene (ATXN2). Noncoding nucleotide repeat expansions in several genes are also associated with neurodegenerative and neuromuscular diseases. For example, hexanucleotide repeat expansions located in a noncoding region of C9ORF72 are the most common cause of ALS. We sought to assess a potential larger role of noncoding nucleotide repeat expansions in ALS...
April 2014: Neurobiology of Aging
R M Castilhos, A F D Souza, G V Furtado, T C Gheno, A L Silva, F R Vargas, M-A F D Lima, O Barsottini, J L Pedroso, C Godeiro, D Salarini, E T Pereira, K Lin, M-B Toralles, J A M Saute, C R Rieder, M Quintas, J Sequeiros, I Alonso, M L Saraiva-Pereira, L B Jardim
The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD-like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral-pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea-acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2-1/TITF1 and VPS13A genes were performed...
October 2014: Clinical Genetics
Irene Paradisi, Vassiliki Ikonomu, Sergio Arias
Huntington disease (HD) phenotypes without a HTT mutation are known as HD-like (HDL) syndromes and are caused by mutations in other loci. HDL2, almost indistinguishable from HD, is due to expansions in the Junctophilin 3 locus (JPH3) with a worldwide Sub-Saharan ethnic origin. Sixteen independent patients with involuntary movements, psychiatric disturbances and ataxia not having a HTT mutation were searched for loci PRNP (prion protein, HDL1), JPH3 (HDL2), ATN1 (dentatorubral-pallidoluysian atrophy), ATX2 (spinocerebellar ataxia 2) ATXN3 (spinocerebellar ataxia 3), and TBP (spinocerebellar ataxia 17=HDL4)...
January 2013: Journal of Human Genetics
Susanne A Schneider, Kate E Marshall, Jianfeng Xiao, Mark S LeDoux
We report the clinical, neuropsychological, genetic, and radiological features of a large five-generation African-American kindred from the southern USA presenting with a progressive akinetic-rigid syndrome and severe dementia, but clinically insignificant chorea, due to mutations in junctophillin 3 (JPH3). Overt disease onset was in the mid-20s to late 30s with cognitive decline, REM sleep disturbance, or psychiatric features, followed by development of a levodopa-unresponsive akinetic-rigid motor syndrome...
May 2012: Neurogenetics
Ana I Seixas, Susan E Holmes, Hiroshi Takeshima, Amira Pavlovich, Nancy Sachs, Jennifer L Pruitt, Isabel Silveira, Christopher A Ross, Russell L Margolis, Dobrila D Rudnicki
OBJECTIVE: Huntington disease-like 2 (HDL2) is a progressive, late onset autosomal dominant neurodegenerative disorder, with remarkable similarities to Huntington disease (HD). HDL2 is caused by a CTG/CAG repeat expansion. In the CTG orientation, the repeat is located within the alternatively spliced exon 2A of junctophilin-3 (JPH3), potentially encoding polyleucine and polyalanine, whereas on the strand antisense to JPH3, the repeat is in frame to encode polyglutamine. The JPH3 protein product serves to stabilize junctional membrane complexes and regulate neuronal calcium flux...
February 2012: Annals of Neurology
Ruth H Walker, Vincent P Schulz, Irina R Tikhonova, Milind C Mahajan, Shrikant Mane, Maritza Arroyo Muniz, Patrick G Gallagher
Neuroacanthocytoses are neurodegenerative disorders marked by phenotypic and genetic heterogeneity. There are several associated genetic loci, and many defects, including gene deletions and insertions, and missense, nonsense, and splicing mutations, have been found spread over hundreds of kilobases of genomic DNA. In some cases, specific diagnosis is unclear, particularly in the early stages of disease or when there is an atypical presentation. Determination of the precise genetic defect allows assignment of the diagnosis and permits carrier detection and genetic counseling...
April 2012: Movement Disorders: Official Journal of the Movement Disorder Society
Brian Wilburn, Dobrila D Rudnicki, Jing Zhao, Tara Murphy Weitz, Yin Cheng, Xiaofeng Gu, Erin Greiner, Chang Sin Park, Nan Wang, Bryce L Sopher, Albert R La Spada, Alex Osmand, Russell L Margolis, Yi E Sun, X William Yang
Huntington's disease-like-2 (HDL2) is a phenocopy of Huntington's disease caused by CTG/CAG repeat expansion at the Junctophilin-3 (JPH3) locus. The mechanisms underlying HDL2 pathogenesis remain unclear. Here we developed a BAC transgenic mouse model of HDL2 (BAC-HDL2) that exhibits progressive motor deficits, selective neurodegenerative pathology, and ubiquitin-positive nuclear inclusions (NIs). Molecular analyses reveal a promoter at the transgene locus driving the expression of a CAG repeat transcript (HDL2-CAG) from the strand antisense to JPH3, which encodes an expanded polyglutamine (polyQ) protein...
May 12, 2011: Neuron
Christine Klein, Susanne A Schneider, Anthony E Lang
In the past decade, a number of genetic causes of parkinsonism have been identified. As a consequence, clinicians have to consider an increasing range of differential diagnoses when confronted with a patient with parkinsonism with a positive family history. While well-established monogenic forms with PARK acronyms have been reviewed extensively, less emphasis has been placed on other inherited conditions that may also present with signs of parkinsonism or even mimic idiopathic Parkinson's disease clinically...
October 30, 2009: Movement Disorders: Official Journal of the Movement Disorder Society
Tetsuro Yoshida, Kimihiko Kato, Kiyoshi Yokoi, Mitsutoshi Oguri, Sachiro Watanabe, Norifumi Metoki, Hidemi Yoshida, Kei Satoh, Yukitoshi Aoyagi, Yoshinori Nozawa, Yoshiji Yamada
Chronic kidney disease (CKD) is recognized as a risk factor not only for end-stage renal disease but also for cardiovascular disease. Early detection and treatment of CKD is a likely key factor for prevention of its complications. Although genetic linkage analyses and association studies have implicated several loci and candidate genes in predisposition to CKD, the genes that underlie genetic susceptibility to this condition have remained largely unknown. The purpose of the present study was to identify genetic variants that confer susceptibility to CKD in Japanese individuals...
October 2009: International Journal of Molecular Medicine
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