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Yoshifusa Abe, Masayuki Iyoda, Kandai Nozu, Satoshi Hibino, Kei Hihara, Yutaka Yamaguchi, Tomohiko Yamamura, Shogo Minamikawa, Kazumoto Iijima, Takanori Shibata, Kazuo Itabashi
We herein report a novel mutation in a Japanese family with an X-linked Alport syndrome (AS) mutation in COL4A5. Patient 1 was a 2-year-old Japanese girl. She and her mother (patient 2) had a history of proteinuria and hematuria without renal dysfunction, deafness, or ocular abnormalities. Pathological findings were consistent with AS, and a genetic analysis revealed that both patients had a heterozygous mutation (c.2767G>C) in exon 32. In summary, the identification of mutations and characteristic pathological findings was useful in making a diagnosis of AS...
2016: Internal Medicine
Judith Savige, Helen Storey, Hae Il Cheong, Hee Gyung Kang, Eujin Park, Pascale Hilbert, Anton Persikov, Carmen Torres-Fernandez, Elisabet Ars, Roser Torra, Jens Michael Hertz, Mads Thomassen, Lev Shagam, Dongmao Wang, Yanyan Wang, Frances Flinter, Mato Nagel
Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset...
2016: PloS One
Barbara Mandriani, Stefano Castellana, Carmela Rinaldi, Marta Manzoni, Santina Venuto, Eva Rodriguez-Aznar, Juan Galceran, M Angela Nieto, Giuseppe Borsani, Eugenio Monti, Tommaso Mazza, Giuseppe Merla, Lucia Micale
To orchestrate the genomic response to cellular stress signals, p53 recognizes and binds to DNA containing specific and well-characterized p53-responsive elements (REs). Differences in RE sequences can strongly affect the p53 transactivation capacity and occur even between closely related species. Therefore, the identification and characterization of a species-specific p53 Binding sistes (BS) consensus sequence and of the associated target genes may help to provide new insights into the evolution of the p53 regulatory networks across different species...
2016: Scientific Reports
Dominic Cosgrove, Shiguang Liu
Alport syndrome is the result of mutations in any of three type IV collagen genes, COL4A3, COL4A4, or COL4A5. Because the three collagen chains form heterotrimers, there is an absence of all three proteins in the basement membranes where they are expressed. In the glomerulus, the mature glomerular basement membrane type IV collagen network, normally comprised of two separate networks, α3(IV)/α4(IV)/α5(IV) and α1(IV)/α2(IV), is comprised entirely of collagen α1(IV)/α2. This review addresses the current state of our knowledge regarding the consequence of this change in basement membrane composition, including both the direct, via collagen receptor binding, and indirect, regarding influences on glomerular biomechanics...
August 27, 2016: Matrix Biology: Journal of the International Society for Matrix Biology
Judy Savige, Yanyan Wang, Andrew Crawford, James Smith, Andrew Symons, Heather Mack, Kathy Nicholls, Diane Wilson, Deb Colville
BACKGROUND AND OBJECTIVES: The retinal features of Alport syndrome include a central and peripheral fleck retinopathy, temporal retinal thinning, and a macular hole. Here we describe further retinal abnormalities. METHODS: We identified a case of bull's eye maculopathy 20 years previously in a 68-year-old female, and reviewed archived retinal images from our cohort of X-linked (28 males, 28 females) or autosomal recessive (n = 13) Alport syndrome. All individuals had Alport syndrome confirmed on genetic testing or renal biopsy, were examined by an ophthalmologist, and underwent retinal imaging (KOWA non-mydriatic camera, Japan)...
August 2, 2016: Ophthalmic Genetics
C P Thomas, M A Mansilla, R Sompallae, S O Mason, C J Nishimura, M J Kimble, C A Campbell, A E Kwitek, B W Darbro, Z A Stewart, R J H Smith
Related living kidney donors (LKDs) are at higher risk of end-stage renal disease (ESRD) compared to unrelated LKDs. A genetic panel was developed to screen 115 genes associated with renal diseases. We used this panel to screen 6 negative controls, 4 transplant candidates with presumed genetic renal disease, and 6 related LKDs. After removing common variants, pathogenicity was predicted using six algorithms to score genetic variants based on conservation and function. All variants were evaluated in the context of patient phenotype and clinical data...
July 19, 2016: American Journal of Transplantation
Zhang Bao, Ran Chen, Pei Zhang, Shan Lu, Xing Chen, Yake Yao, Xiaozheng Jin, Yilan Sun, Jianying Zhou
Mycobacterium tuberculosis (MTB), one of the major bacterial pathogens for lethal infectious diseases, is capable of surviving within the phagosomes of host alveolar macrophages; therefore, host genetic variations may alter the susceptibility to MTB. In this study, to identify host genes exploited by MTB during infection, genes were non-selectively inactivated using lentivirus-based antisense RNA methods in Raw264.7 macrophages, and the cells that survived virulent MTB infection were then screened. Following DNA sequencing of the surviving cell clones, 26 host genes affecting susceptibility to MTB were identified and their pathways were analyzed by bioinformatics analysis...
September 2016: International Journal of Molecular Medicine
Daniel P Gale, D Deren Oygar, Fujun Lin, P Derin Oygar, Nadia Khan, Thomas M F Connor, Marta Lapsley, Patrick H Maxwell, Guy H Neild
BACKGROUND: Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts. METHODS: We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses. RESULTS: We identified a novel frameshift mutation, c.4611_4612insG:p.T1537fs, in exon 49 of COL4A1...
April 8, 2016: Nephrology, Dialysis, Transplantation
Oliver Gross, Clifford E Kashtan, Michelle N Rheault, Frances Flinter, Judith Savige, Jeffrey H Miner, Roser Torra, Elisabet Ars, Constantinos Deltas, Isavella Savva, Laura Perin, Alessandra Renieri, Francesca Ariani, Francesca Mari, Colin Baigent, Parminder Judge, Bertrand Knebelman, Laurence Heidet, Sharon Lagas, Dave Blatt, Jie Ding, Yanqin Zhang, Daniel P Gale, Marco Prunotto, Yong Xue, Asher D Schachter, Lori C G Morton, Jacqui Blem, Michael Huang, Shiguang Liu, Sebastien Vallee, Daniel Renault, Julia Schifter, Jules Skelding, Susie Gear, Tim Friede, A Neil Turner, Rachel Lennon
Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies...
May 10, 2016: Nephrology, Dialysis, Transplantation
Isavella Savva, Alkis Pierides, Constantinos Deltas
Alport syndrome (AS) is a hereditary progressive glomerulonephritis with a high life-time risk for end-stage renal disease (ESRD). Most patients will reach ESRD before the age of 30 years, while a subset of them with milder mutations will do so at older ages, even after 50 years. Frequent extrarenal manifestations are hearing loss and ocular abnormalities. AS is a genetically heterogeneous collagen IV nephropathy, with 85% of the cases caused by mutations in the X-linked COL4A5 gene and the rest by homozygous or compound heterozygous mutations in either the COL4A3 or the COL4A4 gene on chromosome 2q36-37...
May 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Anja Schrade, Antti Kyrönlahti, Oyediran Akinrinade, Marjut Pihlajoki, Simon Fischer, Verena Martinez Rodriguez, Kerstin Otte, Vidya Velagapudi, Jorma Toppari, David B Wilson, Markku Heikinheimo
Conditional deletion of Gata4 in Sertoli cells (SCs) of adult mice has been shown to increase permeability of the blood-testis barrier (BTB) and disrupt spermatogenesis. To gain insight into the molecular underpinnings of these phenotypic abnormalities, we assessed the impact of Gata4 gene silencing in cell culture models. Microarray hybridization identified genes dysregulated by siRNA-mediated inhibition of Gata4 in TM4 cells, an immortalized mouse SC line. Differentially expressed genes were validated by quantitative RT-PCR analysis of primary cultures of Gata4(flox/flox) mouse SCs that had been subjected to cre-mediated recombination in vitro...
June 2016: Endocrinology
Chen Chen, Chao-Xia Lu, Qiong Wang, Li-Hua Cao, Yang Luo, Xue Zhang
AIMS: Alport syndrome (AS) is a genetically heterogeneous disorder, characterized by hematuria, progressive renal failure, sensorineural hearing loss, and ocular abnormalities caused by mutations in the COL4A3, COL4A4, and COL4A5 genes. The aim of this study was to identify underlying mutations in individuals from a Chinese family with X-linked AS. METHODS: We performed targeted next-generation sequencing (NGS) to identify mutations associated with AS. The results were processed and visualized using an Integrated Genomics Viewer software...
April 2016: Genetic Testing and Molecular Biomarkers
Stefanie Weber, Katja Strasser, Sabine Rath, Achim Kittke, Sonja Beicht, Martin Alberer, Bärbel Lange-Sperandio, Peter F Hoyer, Marcus R Benz, Sabine Ponsel, Lutz T Weber, Hanns-Georg Klein, Julia Hoefele
BACKGROUND: Alport syndrome (ATS) is a progressive hereditary nephropathy characterized by hematuria and proteinuria. It can be associated with extrarenal manifestations. In contrast, thin basement membrane nephropathy (TBMN) is characterized by microscopic hematuria, is largely asymptomatic, and is rarely associated with proteinuria and end-stage renal disease. Mutations have been identified in the COL4A5 gene in ATS and in the COL4A3 and COL4A4 genes in ATS and TBMN. To date, more than 1000 different mutations in COL4A5, COL4A3, and COL4A4 are known...
June 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Yanqin Zhang, Jie Ding, Fang Wang, Hongwen Zhang, Huijie Xiao, Yong Yao, Xuhui Zhong, Na Guan, Xiaoyu Liu, Lixia Yu, Jingcheng Liu, Jiyun Yang
OBJECTIVE: To analyze the clinical and genetic features of X-linked Alport syndrome (XLAS) in men positive for the collagen α5(Ⅳ) chain in epidermal basement membrane. METHOD: This was a retrospective study. Totally 725 families were diagnosed as Alport syndrome in Department of Pediatrics of Peking University First Hospital during January 1998 to December 2014, among them 450 patients were males with XLAS. Patients who met both of the following two criteria were included in this study...
January 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Miika Mehine, Eevi Kaasinen, Hanna-Riikka Heinonen, Netta Mäkinen, Kati Kämpjärvi, Nanna Sarvilinna, Mervi Aavikko, Anna Vähärautio, Annukka Pasanen, Ralf Bützow, Oskari Heikinheimo, Jari Sjöberg, Esa Pitkänen, Pia Vahteristo, Lauri A Aaltonen
Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women's health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among leiomyomas harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation of fumarate hydratase (FH), and collagen, type IV, alpha 5 and collagen, type IV, alpha 6 (COL4A5-COL4A6) deletions...
February 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Tao Qiu, Hongyi Wang, Yang Wang, Yu Zhang, Qiang Hui, Kai Tao
The aims of the study were to identify the differentially expressed genes (DEGs) between primary melanomas and metastasis melanomas (MMs), and to investigate the mechanisms of MMs. The microarray data GSE8401 including 31 primary melanomas and 52 MMs were downloaded from Gene Expression Omnibus. DEGs were identified using the Linear Models for Microarray Data package. The functional and pathway enrichment analyses were performed for DEGs. Identification of transcription factors, tumor-associated genes (TAGs), and tumor suppressor genes (TSGs) were performed with the TRANSFAC, TAG, and TSGene databases, respectively...
November 2015: Kaohsiung Journal of Medical Sciences
Jeanne Truong, Georges Deschênes, Patrice Callard, Corinne Antignac, Olivier Niel
BACKGROUND: Alport syndrome (AS) is an inherited glomerular disease associated with hearing and eye defects; its morbidity is a public health issue in developed countries. AS results from mutations in COL4A3, COL4A4, or COL4A5 genes, respectively encoding the alpha-3, alpha-4, and alpha-5 chains of type IV collagen, a major component of the renal glomerular basement membrane (GBM). The diagnosis is usually confirmed by a renal biopsy showing a thinning/thickening of the GBM, with a longitudinal splitting of the lamina densa...
December 1, 2015: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Jeanne Truong, Georges Deschênes, Patrice Callard, Corinne Antignac, Olivier Niel
BACKGROUND: Alport syndrome (AS) is an inherited glomerular disease associated with hearing and eye defects; its morbidity is a public health issue in developed countries. AS results from mutations in COL4A3, COL4A4, or COL4A5 genes, respectively encoding the alpha-3, alpha-4, and alpha-5 chains of type IV collagen, a major component of the renal glomerular basement membrane (GBM). The diagnosis is usually confirmed by a renal biopsy showing a thinning/thickening of the GBM, with a longitudinal splitting of the lamina densa...
December 1, 2015: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Matthias Wuttke, Maximilian Seidl, Angelica Malinoc, Friedrich C Prischl, E Wolfgang Kuehn, Gerd Walz, Anna Köttgen
COL4A5 mutations are a known cause of Alport syndrome, which typically manifests with haematuria, hearing loss and ocular symptoms. Here we report on a 16-year-old male patient with a negative family history who presented with proteinuria, progressive renal failure and haemolysis, but without overt haematuria or hearing loss. A renal biopsy revealed features of atypical IgA nephropathy, while a second biopsy a year later showed features of focal segmental glomerulosclerosis, but was finally diagnosed as chronic thrombotic microangiopathy...
December 2015: Clinical Kidney Journal
Xue Jun Fu, Kandai Nozu, Aya Eguchi, Yoshimi Nozu, Naoya Morisada, Akemi Shono, Mariko Taniguchi-Ikeda, Yuko Shima, Koichi Nakanishi, Igor Vorechovsky, Kazumoto Iijima
BACKGROUND: X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the type IV collagen alpha chain 5 gene (COL4A5). Although many COL4A5 mutations have previously been identified, pathogenic synonymous mutations have not yet been described. METHODS: A family with XLAS underwent mutational analyses of COL4A5 by PCR and direct sequencing, as well as transcript analysis of potential splice site mutations. In silico analysis was also conducted to predict the disruption of splicing factor binding sites...
October 2016: Clinical and Experimental Nephrology
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