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Kunwar Jung-Kc, Nastassja Himmelreich, Karina S Prestegård, Tie-Jun Sten Shi, Tanja Scherer, Ming Ying, Ana Jorge-Finnigan, Beat Thöny, Nenad Blau, Aurora Martinez
DNAJC12, a type III member of the HSP40/DNAJ family, has been identified as the specific co-chaperone of phenylalanine hydroxylase (PAH) and the other aromatic amino acid hydroxylases. DNAJ proteins work together with molecular chaperones of the HSP70-family to assist in proper folding and maintenance of intracellular stability of their clients. Autosomal recessive mutations in DNAJC12 were found to reduce PAH levels, leading to hyperphenylalaninemia (HPA) in patients without mutations in PAH. In this work we investigated the interaction of normal wild-type DNAJC12 with mutant PAH in cells expressing several PAH variants associated with HPA in humans, as well as in the Enu1/1 mouse model, homozygous for the V106A-Pah variant, which leads to severe protein instability, accelerated PAH degradation and mild HPA...
January 22, 2019: Human Mutation
Rosa Navarrete, Fátima Leal, Ana I Vega, Ana Morais-López, María Teresa Garcia-Silva, Elena Martín-Hernández, Pilar Quijada-Fraile, Ana Bergua, Inmaculada Vives, Inmaculada García-Jiménez, Raquel Yahyaoui, Consuelo Pedrón-Giner, Amaya Belanger-Quintana, Sinziana Stanescu, Elvira Cañedo, Oscar García-Campos, María Bueno-Delgado, Carmen Delgado-Pecellín, Isidro Vitoria, María Dolores Rausell, Elena Balmaseda, Mari Luz Couce, Lourdes R Desviat, Begoña Merinero, Pilar Rodríguez-Pombo, Magdalena Ugarte, Celia Pérez-Cerdá, Belén Pérez
The present work describes the value of genetic analysis as a confirmatory measure following the detection of suspected inborn errors of metabolism in the Spanish newborn mass spectrometry screening program. One hundred and forty-one consecutive DNA samples were analyzed by next-generation sequencing using a customized exome sequencing panel. When required, the Illumina extended clinical exome panel was used, as was Sanger sequencing or transcriptional profiling. Biochemical tests were used to confirm the results of the genetic analysis...
January 9, 2019: European Journal of Human Genetics: EJHG
Yasuo Uno, Mitsuro Kanda, Takashi Miwa, Shinichi Umeda, Haruyoshi Tanaka, Chie Tanaka, Daisuke Kobayashi, Masaya Suenaga, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera
BACKGROUND: Identification of gastric cancer-related molecules is necessary to elucidate the pathological mechanisms of this heterogeneous disease. The purpose of this study was to identify novel genes associated with aggressive phenotypes of gastric cancer. METHODS: Global expression profiling was conducted using tissues from four patients with metastatic gastric cancer to identify genes overexpressed in gastric cancer. Fifteen gastric cell lines and 262 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis...
January 7, 2019: Annals of Surgical Oncology
Heiko Brennenstuhl, Sabine Jung-Klawitter, Birgit Assmann, Thomas Opladen
Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH4 ). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin...
October 29, 2018: Neuropediatrics
Yi Feng, Sichi Liu, Chengfang Tang, Xiang Jiang, Fang Tang, Bei Li, Xuefang Jia, Qianyu Chen, Jilian Liu, Yonglan Huang
Hyperphenylalaninemia (HPA), an abnormal condition of phenylalanine metabolism, was recently reported to be caused by DNAJC12 mutations. As the heat shock co-chaperone, DNAJC12 prevents the aggregation of misfolded or aggregation-prone proteins and maintain the correct assembly and degradation. Here, we report a patient with unexplained HPA detected by newborn screening. Differential diagnoses of pterin profile and targeted next generation sequencing of excluded the most common causes of the defects of the enzyme phenylalanine hydroxylase or its cofactor tetrahydrobiopterin (BH4)...
September 1, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Danielle Veenma, Dawn Cordeiro, Neal Sondheimer, Saadet Mercimek-Andrews
Hyperphenylalaninemia, movement disorder, and intellectual disability due to variants in DNAJC12 is a recently reported inherited neurotransmitter disorder. We report two new patients with this new genetic disorder. Patient 1 is a 6-year-11-month-old boy with mild hyperphenylalaninemia and global developmental delay (GDD). Seventeen-year-old male sibling of patient 1 had GDD from the first year of life. He had mild hyperphenylalaninemia at 11.5 years of age following his younger brother's diagnosis. He had low levels of homovanillic acid and 5-hydroxyindolacetic acid in the cerebrospinal fluid...
December 2018: European Journal of Human Genetics: EJHG
Christina K Cajigas-Du Ross, Shannalee R Martinez, Leanne Woods-Burnham, Alfonso M Durán, Sourav Roy, Anamika Basu, Joshua A Ramirez, Greisha L Ortiz-Hernández, Leslimar Ríos-Colón, Evgeny Chirshev, Evelyn S Sanchez-Hernandez, Ubaldo Soto, Celine Greco, Claude Boucheix, Xin Chen, Juli Unternaehrer, Charles Wang, Carlos A Casiano
Patients with metastatic castration-resistant prostate cancer (mCRPC) develop resistance to conventional therapies including docetaxel (DTX). Identifying molecular pathways underlying DTX resistance is critical for developing novel combinatorial therapies to prevent or reverse this resistance. To identify transcriptomic signatures associated with acquisition of chemoresistance we profiled gene expression in DTX-sensitive and -resistant mCRPC cells using RNA sequencing (RNA-seq). PC3 and DU145 cells were selected for DTX resistance and this phenotype was validated by immunoblotting using DTX resistance markers (e...
July 13, 2018: Oncotarget
Wenting Dai, Quanjuan Wang, Fengqi Zhao, Jianxin Liu, Hongyun Liu
BACKGROUND: Bovine milk is an important nutrient source for humans. Forage plays a vital role in dairy husbandry via affecting milk quality and quantity. However, the differences in mammary metabolism of dairy cows fed different forages remain elucidated. In this study, we utilized transcriptomic RNA-seq and iTRAQ proteomic techniques to investigate and integrate the differences of molecular pathways and biological processes in the mammary tissues collected from 12 lactating cows fed corn stover (CS, low-quality, n = 6) and alfalfa hay (AH, high-quality, n = 6)...
May 29, 2018: BMC Genomics
Yu Fan, Zhi-Hua Yang, Fang Li, Xin-Chao Hu, Yi-Wei Yue, Jing Yang, Yu-Tao Liu, Han Liu, Yan-Lin Wang, Chang-He Shi, Yu-Ming Xu
Recently, mutations of DNAJC12 gene were reported to be associated with early-onset parkinsonism, progressive neurodevelopmental delay, and dystonia in several unrelated pedigrees. This study aimed to evaluate DNAJC12 coding mutations in sporadic Chinese Han patients with Parkinson's disease (PD) and test whether an age-of-onset effect exists. Seven hundred two Chinese Han sporadic PD patients, including 181 early-onset PD and 521 late-onset PD, and 728 healthy controls were recruited. No documented disease-causing mutation of DNAJC12 was identified, but we found 7 single-nucleotide polymorphisms...
August 2018: Neurobiology of Aging
Juliette Bouchereau, Edward L Huttlin, Virginia Guarani, Samia Pichard, Yair Anikster, Manuel Schiff
No abstract text is available yet for this article.
March 2018: Molecular Genetics and Metabolism
Monique G M de Sain-van der Velden, Willemijn F E Kuper, Marie-Anne Kuijper, Lenneke A T van Kats, Hubertus C M T Prinsen, Astrid C J Balemans, Gepke Visser, Koen L I van Gassen, Peter M van Hasselt
BACKGROUND: Biallelic mutations in DNAJC12 were recently identified as a BH4 -responsive cause of hyperphenylalaninemia (HPA). Outcome was only favorable when treatment was initiated early in life. We report on a 15-year-old boy with HPA due to a homozygous deletion in DNAJC12 in whom - despite his advanced age - treatment was initiated. CASE: A boy with developmental delay, an extrapyramidal movement disorder, and persistently elevated plasma phenylalanine levels was diagnosed with DNAJC12 deficiency at the age of 15 years...
2018: JIMD Reports
Nenad Blau, Aurora Martinez, Georg F Hoffmann, Beat Thöny
Patients with hyperphenylalaninemia (HPA) are detected through newborn screening for phenylketonuria (PKU). HPA is known to be caused by deficiencies of the enzyme phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4 ). Current guidelines for the differential diagnosis of HPA would, however, miss a recently described DNAJC12 deficiency. The co-chaperone DNAJC12 is, together with the 70kDa heat shock protein (HSP70), responsible for the proper folding of PAH. All DNAJC12-deficient patients investigated to date responded to a challenge with BH4 by lowering their blood phenylalanine levels...
January 2018: Molecular Genetics and Metabolism
Letizia Straniero, Ilaria Guella, Roberto Cilia, Laura Parkkinen, Valeria Rimoldi, Alexander Young, Rosanna Asselta, Giulia Soldà, Vesna Sossi, A Jon Stoessl, Alberto Priori, Kenya Nishioka, Nobutaka Hattori, Jordan Follett, Alex Rajput, Nenad Blau, Gianni Pezzoli, Matthew J Farrer, Stefano Goldwurm, Ali H Rajput, Stefano Duga
Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T;p.K63* and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology, and substantia nigra depigmentation with moderate cell loss...
October 2017: Annals of Neurology
Francjan J van Spronsen, Nastassja Himmelreich, Véronique Rüfenacht, Nan Shen, Danique van Vliet, Mohammed Al-Owain, Khushnooda Ramzan, Salwa M Alkhalifi, Roelineke J Lunsing, Rebecca M Heiner-Fokkema, Anahita Rassi, Corinne Gemperle-Britschgi, Georg F Hoffmann, Nenad Blau, Beat Thöny
BACKGROUND: Autosomal recessive mutations in DNAJC12, encoding a cochaperone of HSP70 with hitherto unknown function, were recently described to lead to hyperphenylalaninemia, central monoamine neurotransmitter (dopamine and serotonin) deficiency, dystonia and intellectual disability in six subjects affected by homozygous variants. OBJECTIVE: Patients exhibiting hyperphenylalaninemia in whom deficiencies in hepatic phenylalanine hydroxylase and tetrahydrobiopterin cofactor metabolism had been excluded were subsequently analysed for DNAJC12 variants...
August 9, 2017: Journal of Medical Genetics
Yair Anikster, Tobias B Haack, Thierry Vilboux, Ben Pode-Shakked, Beat Thöny, Nan Shen, Virginia Guarani, Thomas Meissner, Ertan Mayatepek, Friedrich K Trefz, Dina Marek-Yagel, Aurora Martinez, Edward L Huttlin, Joao A Paulo, Riccardo Berutti, Jean-François Benoist, Apolline Imbard, Imen Dorboz, Gali Heimer, Yuval Landau, Limor Ziv-Strasser, May Christine V Malicdan, Corinne Gemperle-Britschgi, Kirsten Cremer, Hartmut Engels, David Meili, Irene Keller, Rémy Bruggmann, Tim M Strom, Thomas Meitinger, James C Mullikin, Gerard Schwartz, Bruria Ben-Zeev, William A Gahl, J Wade Harper, Nenad Blau, Georg F Hoffmann, Holger Prokisch, Thomas Opladen, Manuel Schiff
Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH4 ) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH4 metabolism disorder-related genes...
February 2, 2017: American Journal of Human Genetics
Suresh Vatakuti, Jeroen L A Pennings, Emilia Gore, Peter Olinga, Geny M M Groothuis
Human toxicity screening is an important stage in the development of safe drug candidates. Hepatotoxicity is one of the major reasons for the withdrawal of drugs from the market because the liver is the major organ involved in drug metabolism, and it can generate toxic metabolites. There is a need to screen molecules for drug-induced hepatotoxicity in humans at an earlier stage. Transcriptomics is a technique widely used to screen molecules for toxicity and to unravel toxicity mechanisms. To date, the majority of such studies were performed using animals or animal cells, with concomitant difficulty in interpretation due to species differences, or in human hepatoma cell lines or cultured hepatocytes, suffering from the lack of physiological expression of enzymes and transporters and lack of nonparenchymal cells...
March 21, 2016: Chemical Research in Toxicology
Hong-Lin He, Ying-En Lee, Hsin-Pao Chen, Chung-Hsi Hsing, I-Wei Chang, Yow-Ling Shiue, Sung-Wei Lee, Chao-Tien Hsu, Li-Ching Lin, Ting-Feng Wu, Chien-Feng Li
Genes associated with protein folding have been found to have certain prognostic significance in a subset of cancers. The aim of this study is to evaluate the clinical impact of DNAJC12 expression in patients with rectal cancers receiving neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery. Through data mining from a public transcriptomic dataset of rectal cancer focusing on genes associated with protein folding, we found that DNAJC12, a member of the HSP40/DNAJ family, was the most significant such gene correlated with the CCRT response...
June 2015: Experimental and Molecular Pathology
Jin Choi, Sonia Djebbar, Andréa Fournier, Claude Labrie
Human DNAJC12 is a J domain-containing protein whose regulation, subcellular localization, and function are currently unknown. We show here that the abundance of DNAJC12 in human LNCaP prostate cancer cells is upregulated by the stress-inducing drug A23187 and by the stressregulated transcription factor AIbZIP/CREB3L4. The DNAJC12 gene encodes two isoforms, only one of which (isoform a) is expressed in these cells. Immunofluorescence studies showed that a recombinant DNAJC12 protein is diffusely distributed in the cytoplasm...
May 2014: Cell Stress & Chaperones
V Bubnov, E Moskalev, Y Petrovskiy, A Bauer, J Hoheisel, V Zaporozhan
AIM: Breast cancer (BC) is one of the most common forms of cancer amongst females. Early diagnosis, prognosis and therapy plays crucial role in the survival of patients with breast cancer. The study was aimed on identification of potential markers for early BC diagnostics by means of genome-wide comparative analysis of gene expression in cancer and normal tissue of breast. METHODS: The analysis of gene expression in 15 invasive adenocarcinoma specimens and 15 normal breast tissue was conducted using the full-genome microarrays Sentrix HumanWD-6V3 BeadChip (Illumina)...
December 2012: Experimental Oncology
David Euhus, Dawei Bu, Xian-Jin Xie, Venetia Sarode, Raheela Ashfaq, Kelly Hunt, Weiya Xia, Joyce O'Shaughnessy, Michael Grant, Banu Arun, William Dooley, Alexander Miller, David Flockhart, Cheryl Lewis
Five years of tamoxifen reduces breast cancer risk by nearly 50% but is associated with significant side effects and toxicities. A better understanding of the direct and indirect effects of tamoxifen in benign breast tissue could elucidate new mechanisms of breast carcinogenesis, suggest novel chemoprevention targets, and provide relevant early response biomarkers for phase II prevention trials. Seventy-three women at increased risk for breast cancer were randomized to tamoxifen (20 mg daily) or placebo for 3 months...
November 2011: Cancer Prevention Research
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