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JOURNAL ARTICLE
Sekita Dalsgård Petersen, Mohamed Belmouhand, Jens Michael Hertz, Christina Fagerberg, Charlotte Brasch-Andersen, Jakob Grauslund, Francis L Munier, Michael Larsen
BACKGROUND: We report a three-generation family with isolated Alport-like retinal abnormalities in the absence of lenticonus, hearing loss, kidney disease, and detectable molecular genetic defects in known Alport-related genes. METHODS: Clinical examination includes ocular biomicroscopy, fundus photography, optical coherence tomography, dipstick urinalysis, serum creatinine assessment, and molecular genetic analysis. RESULTS: The proband, her mother, and her maternal grandmother had normal best-corrected visual acuity and normal visual fields in both eyes...
January 10, 2024: Ophthalmic Genetics
#22
Valentina Cipriani, Letizia Vestito, Emma F Magavern, Julius Ob Jacobsen, Gavin Arno, Elijah R Behr, Katherine A Benson, Marta Bertoli, Detlef Bockenhauer, Michael R Bowl, Kate Burley, Li F Chan, Patrick Chinnery, Peter Conlon, Marcos Costa, Alice E Davidson, Sally J Dawson, Elhussein Elhassan, Sarah E Flanagan, Marta Futema, Daniel P Gale, Sonia García-Ruiz, Cecilia Gonzalez Corcia, Helen R Griffin, Sophie Hambleton, Amy R Hicks, Henry Houlden, Richard S Houlston, Sarah A Howles, Robert Kleta, Iris Lekkerkerker, Siying Lin, Petra Liskova, Hannah Mitchison, Heba Morsy, Andrew D Mumford, William G Newman, Ruxandra Neatu, Edel A O'Toole, Albert Cm Ong, Alistair T Pagnamenta, Shamima Rahman, Neil Rajan, Peter N Robinson, Mina Ryten, Omid Sadeghi-Alavijeh, John A Sayer, Claire L Shovlin, Jenny C Taylor, Omri Teltsh, Ian Tomlinson, Arianna Tucci, Clare Turnbull, Albertien M van Eerde, James S Ware, Laura M Watts, Andrew R Webster, Sarah K Westbury, Sean L Zheng, Mark Caulfield, Damian Smedley
To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more...
December 21, 2023: medRxiv
#23
JOURNAL ARTICLE
Thomas Robert, Laure Raymond, Marine Dancer, Julia Torrents, Noémie Jourde-Chiche, Stéphane Burtey, Christophe Béroud, Laurent Mesnard
BACKGROUND: According to data from large national registries, almost 20%-25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate. METHODS: ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021...
January 2024: Clinical Kidney Journal
#24
JOURNAL ARTICLE
Teresa Bada-Bosch, Angel M Sevillano, María Teresa Sánchez-Calvin, Carmen Palma-Milla, Ignacio Alba de Cáceres, Francisco Díaz-Crespo, Hernando Trujillo, Marina Alonso, Clara Cases-Corona, Amir Shabaka, Juan Francisco Quesada-Espinosa, José Miguel Lezana Rosales, Eduardo Gutiérrez, Gema Fernández-Juárez, Fernando Caravaca-Fontán, Manuel Praga
BACKGROUND AND HYPOTHESIS: Autosomal Dominant Alport Syndrome (ADAS), also known as Thin Basement Membrane Disease (TBMD), is caused by pathogenic variants in COL4A3 and COL4A4 genes. A cystic phenotype has been described in some patients with TBMD, but no genetic studies were performed. We conducted a genetic and radiologic investigation in a cohort of ADAS patients to analyze the prevalence of multicystic kidney disease (MKD) and its association with Chronic Kidney Disease (CKD). METHODS: Retrospective single-center cohort study...
January 4, 2024: Nephrology, Dialysis, Transplantation
#25
JOURNAL ARTICLE
Precil D Neves, Andreia Watanabe, Elieser H Watanabe, Amanda M Narcizo, Kelly Nunes, Antonio M Lerario, Frederico Moraes Ferreira, Lívia B Cavalcante, Janewit Wongboonsin, Denise M Malheiros, Lectícia B Jorge, Matthew G Sampsom, Irene L Noronha, Luiz F Onuchic
Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically-admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis...
December 22, 2023: Kidney International
#26
JOURNAL ARTICLE
Kevin Tröndle, Ludovica Rizzo, Roman Pichler, Stefan Zimmermann, Soeren S Lienkamp
Flow-induced shear stress affects renal epithelial cells in the nephron tubule with potential implications for differential functionalities of the individual segments. Disruptions of cellular mechanosensation or flow conditions are associated with the development and progression of various renal diseases. This study investigates the effects of flow on the transcriptome of various renal tubular epithelial cell types. We analyzed the transcriptome of induced renal epithelial cells (iREC) cultured under physiological flow (0...
January 2024: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
#27
JOURNAL ARTICLE
Xiaoli Gao, Meilu Li, Kan Wang, Zengyan Li, Cha Han
RATIONALE: Autosomal recessive Alport syndrome (ARAS) is an hereditary heterogeneous disease that poses a serious risk to pregnant women. PATIENT CONCERNS: We reported 2 cases of pregnancy with progressive proteinuria. The case 1 was a 21-year-old woman with 24-h proteinuria increased from 2.03 to 11.72 g at 13 to 35 weeks of gestation, and the case 2 was a 28-year-old woman with 24-h proteinuria increased from 2.10 to 9.32 g at 8 to 36 weeks of gestation...
November 17, 2023: Medicine (Baltimore)
#28
JOURNAL ARTICLE
Elena N Pokidysheva, Neve Redhair, Octavia Ailsworth, Patrick Page-McCaw, Louise Rollins-Smith, Vijayishwer Singh Jamwal, Yuko Ohta, Hans Peter Bächinger, Prayag Murawala, Martin Flajnik, Agnes B Fogo, Dale Abrahamson, Julie K Hudson, Sergei P Boudko, Billy G Hudson
The collagen IVα345 (Col-IVα345 ) scaffold, the major constituent of the glomerular basement membrane (GBM), is a critical component of the kidney glomerular filtration barrier. In chronic kidney disease, affecting hundreds of millions of people worldwide, over two thousand genetic variants occur in the COL4A3, COL4A4, and COL4A5 genes that encode the Col-IVα345 scaffold. Variants cause loss of scaffold, a supra-structure that tethers macromolecules, from the GBM or assembly of a defective scaffold, causing hematuria in nearly all cases, proteinuria and often progressive kidney failure...
November 15, 2023: Journal of Biological Chemistry
#29
JOURNAL ARTICLE
Ana María Tato, Noa Carrera, Maria García-Murias, Amir Shabaka, Ana Ávila, María Teresa Mora Mora, Cristina Rabasco, Karina Soto, Francisco Jose de la Prada Alvarez, Loreto Fernández-Lorente, Antolina Rodríguez-Moreno, Ana Huerta, Carmen Mon, Clara García-Carro, Fayna González Cabrera, Juan Antonio Martín Navarro, Ana Romera, Eduardo Gutiérrez, Javier Villacorta, Alberto de Lorenzo, Beatriz Avilés, Miguel Angel Garca-González, Gema Fernández-Juárez
BACKGROUND: Genetic causes are increasingly recognized in patients with focal segmental glomerulosclerosis (FSGS), but it remains unclear which patients should undergo genetic study. Our objective was to determine the frequency and distribution of genetic variants in steroid-resistant nephrotic syndrome FSGS (SRNS-FSGS) and in FSGS of undetermined cause (FSGS-UC). METHODS: We performed targeted exome sequencing of 84 genes associated with glomerulopathy in patients with adult-onset SRNS-FSGS or FSGS-UC after ruling out secondary causes...
November 2023: Clinical Kidney Journal
#30
Patrick S Page-McCaw, Elena N Pokidysheva, Carl E Darris, Sergei Chetyrkin, Aaron L Fidler, Prayag Murawala, Julianna Gallup, Julie K Hudson, Billy G Hudson
Collagen IV is a primordial component of basement membranes, a specialized form of extracellular matrix that enabled multi-cellular epithelial tissues. In mammals, collagen IV assembles from a family of six α-chains (α1 to α6), encoded by six genes (COL4A1 to COL4A6), into three distinct scaffolds: the α121, the α345 and a mixed scaffold containing both α121 and α565. The six mammalian COL4A genes occur in pairs that occur in a head-to-head arrangement on three distinct chromosomes...
October 21, 2023: bioRxiv
#31
JOURNAL ARTICLE
Jonathan E Zuckerman, Rachana Srivastava
Alport syndrome is a genetically and phenotypically heterogeneous disorder that can be transmitted in an X-linked, autosomal recessive, or autosomal dominant fashion and can affect glomerular, cochlear, and ocular basement membranes. The disorder results from mutations in the collagen IV genes COL4A5 (X chromosome), COL4A3 , and COL4A4 . Alport patients are at lifetime risk for kidney failure, sensorineural deafness, and ocular abnormalities. Males with Alport syndrome typically present with severe phenotype with progression to end-stage kidney disease and/or sensorineural deafness and eye changes...
2023: Glomerular diseases
#32
JOURNAL ARTICLE
Aziz Suat Gunsel, Mahmut Cerkez Ergoren, Hatice Kemal, Haniyeh Rahbar Kafshboran, Levent Cerit, Ayla Turgay, Hamza Duygu
Whole-exome DNA sequencing is a rich source of clinically useful information for specialists, patients, and their families, as well as elucidating the genetic basis of monogenic and complex diseases in clinical diagnosis. However, interpreting and reporting variants encompassing exome and genome sequence analysis outcome data are one of the greatest challenges of the genomic era. In this study, we aimed to investigate the frequency and allele frequency spectrum of single nucleotide variants accepted as recessive disease carrier status in Turkish Cypriot exomes...
October 20, 2023: Genes
#33
REVIEW
A Current Landscape on Alport Syndrome Cases: Characterization, Therapy and Management Perspectives.
Nahed N Mahrous, Yahya F Jamous, Ahmad M Almatrafi, Deema I Fallatah, Abdulrahman Theyab, Bayan H Alanati, Suliman A Alsagaby, Munifa K Alenazi, Mohammed I Khan, Yousef M Hawsawi
Alport syndrome (AS) is a rare genetic disorder categorized by the progressive loss of kidney function, sensorineural hearing loss and eye abnormalities. It occurs due to mutations in three genes that encode for the alpha chains of type IV collagen. Globally, the disease is classified based on the pattern of inheritance into X-linked AS (XLAS), which is caused by pathogenic variants in COL4A5, representing 80% of AS. Autosomal recessive AS (ARAS), caused by mutations in either COL4A3 or COL4A4, represents 15% of AS...
October 12, 2023: Biomedicines
#34
JOURNAL ARTICLE
Sarah A Gagliano Taliun, Ian R Dinsmore, Tooraj Mirshahi, Alexander R Chang, Andrew D Paterson, Moumita Barua
Our GWAS of hematuria in the UK Biobank identified 6 loci, some of which overlap with loci for albuminuria suggesting pleiotropy. Since clinical syndromes are often defined by combinations of traits, generating a combined phenotype can improve power to detect loci influencing multiple characteristics. Thus the composite trait of hematuria and albuminuria was chosen to enrich for glomerular pathologies. Cases had both hematuria defined by ICD codes and albuminuria defined as uACR > 3 mg/mmol...
October 23, 2023: Scientific Reports
#35
JOURNAL ARTICLE
Thomas Robert, Sophie Greillier, Julia Torrents, Laure Raymond, Marine Dancer, Noémie Jourde-Chiche, Jean-Michel Halimi, Stéphane Burtey, Christophe Béroud, Laurent Mesnard
INTRODUCTION: Previous studies have suggested that genetic kidney diseases in adults are often overlooked, representing up to 10% of all cases of chronic kidney disease (CKD). We present data obtained from exome sequencing (ES) analysis of patients with biopsy-proven undetermined kidney disease (UKD). METHODS: ES was proposed during routine clinical care in patients with UKD from January 2020 to December 2021. We used in silico custom kidney genes panel analysis to detect pathological variations using American College of Medical Genetics guidelines in 52 patients with biopsy-proven UKD with histological finding reassessment...
October 2023: KI Reports
#36
JOURNAL ARTICLE
Kaushal V Solanki, Yirui Hu, Bryn S Moore, Vida Abedi, Venkatesh Avula, Tooraj Mirshahi, Natasha T Strande, Ion D Bucaloiu, Alexander R Chang
INTRODUCTION: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied. METHODS: Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review...
October 2023: KI Reports
#37
JOURNAL ARTICLE
Rundong Lv, Lei Duan, Jie Gao, Jigang Si, Chen Feng, Jun Hu, Xiulan Zheng
INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease involving many systems and organs, and individuals with SLE exhibit unique cancer risk characteristics. The significance of the basement membrane (BM) in the occurrence and progression of human autoimmune diseases and tumors has been established through research. However, the roles of BM-related genes and their protein expression mechanisms in the pathogenesis of SLE and pan-cancer development has not been elucidated...
2023: Frontiers in Immunology
#38
JOURNAL ARTICLE
Ryuichiro Hirayama, Kosuke Toyohara, Kei Watanabe, Takeya Otsuki, Toshikazu Araoka, Shin-Ichi Mae, Tomoko Horinouchi, Tomohiko Yamamura, Keisuke Okita, Akitsu Hotta, Kazumoto Iijima, Kandai Nozu, Kenji Osafune
Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vitro methods for testing the restoration of normal GBMs. Here, we aimed to develop kidney organoid models from AS patient iPSCs for this purpose. We established iPSC-derived collagen α5(IV)-expressing kidney organoids and confirmed that kidney organoids from COL4A5 mutation-corrected iPSCs restore collagen α5(IV) protein expression...
September 28, 2023: Communications Biology
#39
REVIEW
Constantinos Deltas, Gregory Papagregoriou, Stavroula F Louka, Apostolos Malatras, Frances Flinter, Daniel P Gale, Susie Gear, Oliver Gross, Julia Hoefele, Rachel Lennon, Jeffrey H Miner, Alessandra Renieri, Judy Savige, A Neil Turner
Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, COL4A3/A4/A5 . Pathogenic variants in COL4A5 are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the COL4A3 or the COL4A4 gene cause autosomal recessive AS. AS usually leads to progressive kidney failure before the age of 40-years when left untreated...
August 25, 2023: Genes
#40
Yu-Ting Chen, Wen-Ze Jiang, Ke-Da Lu
BACKGROUND: Alport syndrome (AS) is an inherited disease of the glomerular basement membrane caused by mutations in genes encoding α3, α4, or α5 chains of type IV collagen. It manifests with hematuria or proteinuria, which is often accompanied by hearing impairments and ocular abnormalities. Histopathologically, AS shows mesangial proliferation and sometimes incidental immunoglobulin A (IgA) deposition. Hematuria or proteinuria is also a common presentation in patients with IgA nephropathy that makes it difficult to differentially diagnose AS and IgA nephropathy solely based on these clinical and pathological features...
September 6, 2023: World Journal of Clinical Cases
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