|
1
|
Riedhammer KM, Simmendinger H, Tasic V, Putnik J, Abazi-Emini N, Stajic N, Berutti R, Weidenbusch M, Patzer L, Lungu A, Milosevski-Lomic G, Günthner R, Braunisch MC, Ćomić J, Hoefele J. Is there a dominant-negative effect in individuals with heterozygous disease-causing variants in COL4A3/COL4A4? Clin Genet 2024; 105:406-414. [PMID: 38214412 DOI: 10.1111/cge.14471] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 01/13/2024]
Abstract
Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature.
Collapse
Affiliation(s)
- Korbinian M Riedhammer
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
| | - Hannes Simmendinger
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
| | - Velibor Tasic
- Medical Faculty of Skopje, University Children's Hospital, Macedonia
| | - Jovana Putnik
- Institute for Mother and Child Health Care of Serbia "Dr Vukan Čupić", Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade, Serbia
| | - Nora Abazi-Emini
- Medical Faculty of Skopje, University Children's Hospital, Macedonia
| | - Natasa Stajic
- Institute for Mother and Child Health Care of Serbia "Dr Vukan Čupić", Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade, Serbia
| | - Riccardo Berutti
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
| | - Marc Weidenbusch
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany
| | - Ludwig Patzer
- Department of Pediatric Nephrology, Children's Hospital St. Elisabeth and St. Barbara, Halle/Saale, Germany
| | - Adrian Lungu
- Pediatric Nephrology Department, Fundeni Clinical Institute, Bucharest, Romania
| | - Gordana Milosevski-Lomic
- Institute for Mother and Child Health Care of Serbia "Dr Vukan Čupić", Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade, Serbia
| | - Roman Günthner
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
| | - Matthias C Braunisch
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
| | - Jasmina Ćomić
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
| | - Julia Hoefele
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany
| |
Collapse
|
|
2
|
Chen YT, Jiang WZ, Lu KD. Novel COL4A3 synonymous mutation causes Alport syndrome coexistent with immunoglobulin A nephropathy in a woman: A case report. World J Clin Cases 2023; 11:5947-5953. [PMID: 37727481 PMCID: PMC10506036 DOI: 10.12998/wjcc.v11.i25.5947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/31/2023] [Accepted: 08/08/2023] [Indexed: 09/01/2023] Open
Abstract
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. CASE SUMMARY Herein, we present the case of a 59-year-old female patient who was admitted to our hospital with persistent microscopic hematuria and occasional proteinuria that had lasted for > 2 years. This patient had a familial history of renal disease and was diagnosed with autosomal dominant AS (ADAS) and IgA nephropathy based on the findings of renal biopsy as well as genetic testing performed using whole-exome sequencing, which suggested that the patient carried a novel heterozygous variation (c.888G>A:p.Gln296Gln) in the COL4A3 gene that enriches the mutation spectrum of ADAS. The proband received an angiotensin receptor blocker therapy after a definitive diagnosis was established. After one year of therapy, a significant reduction in proteinuria was observed. The number of microscopic red blood cells per high-power field decreased to one-quarter of the baseline levels. Renal function also maintained well during the follow-up. CONCLUSION Our case highlights the significance of performing kidney biopsy and genetic testing in the diagnosis of AS and familial IgA nephropathy.
Collapse
Affiliation(s)
- Yu-Ting Chen
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Wen-Ze Jiang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Ke-Da Lu
- Department of Nephrology, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
| |
Collapse
|
|
3
|
Ćomić J, Riedhammer KM, Günthner R, Schaaf CW, Richthammer P, Simmendinger H, Kieffer D, Berutti R, Tasic V, Abazi-Emini N, Nushi-Stavileci V, Putnik J, Stajic N, Lungu A, Gross O, Renders L, Heemann U, Braunisch MC, Meitinger T, Hoefele J. The multifaceted phenotypic and genotypic spectrum of type-IV-collagen-related nephropathy—A human genetics department experience. Front Med (Lausanne) 2022; 9:957733. [PMID: 36117978 PMCID: PMC9470833 DOI: 10.3389/fmed.2022.957733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/29/2022] [Indexed: 11/28/2022] Open
Abstract
Disease-causing variants in COL4A3-5 are associated with type-IV-collagen-related nephropathy, a genetically and phenotypically multifaceted disorder comprising Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) and autosomal, X-linked and a proposed digenic inheritance. Initial symptoms of individuals with AS are microscopic hematuria followed by proteinuria leading to kidney failure (90% on dialysis < age 40 years). In contrast, individuals with TBMN, an outdated histology-derived term, present with microscopic hematuria, only some of them develop kidney failure (>50 years of age). An early diagnosis of type-IV-collagen-related nephropathy is essential for optimized therapy and slowing of the disease. Sixty index cases, in whom exome sequencing had been performed and with disease-causing variant(s) in COL4A3-5, were evaluated concerning their clinical tentative diagnosis and their genotype. Of 60 reevaluated individuals with type-IV-collagen-related nephropathy, 72% had AS, 23% TBMN and 5% focal segmental glomerulosclerosis (FSGS) as clinical tentative diagnosis. The FSGS cases had to be re-classified as having type-IV-collagen-related nephropathy. Twelve percent of cases had AS as clinical tentative diagnosis and a monoallelic disease-causing variant in COL4A3/4 but could not be classified as autosomal dominant AS because of limited or conflicting clinical data. This study illustrates the complex clinical and genetic picture of individuals with a type IV-collagen-related nephropathy indicating the need of a refined nomenclature and the more interdisciplinary teamwork of clinicians and geneticists as the key to optimized patient care.
Collapse
Affiliation(s)
- Jasmina Ćomić
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Korbinian M. Riedhammer
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Roman Günthner
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Christian W. Schaaf
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Patrick Richthammer
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Hannes Simmendinger
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Donald Kieffer
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Riccardo Berutti
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Velibor Tasic
- University Children's Hospital, Medical Faculty of Skopje, Skopje, North Macedonia
| | - Nora Abazi-Emini
- University Children's Hospital, Medical Faculty of Skopje, Skopje, North Macedonia
| | | | - Jovana Putnik
- Institute for Mother and Child Health Care of Serbia “Dr. Vukan Čupić”, Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade, Serbia
| | - Nataša Stajic
- Institute for Mother and Child Health Care of Serbia “Dr. Vukan Čupić”, Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade, Serbia
| | - Adrian Lungu
- University Children's Hospital, Medical Faculty of Skopje, Skopje, North Macedonia
| | - Oliver Gross
- Clinic of Nephrology and Rheumatology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany
| | - Lutz Renders
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Uwe Heemann
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Matthias C. Braunisch
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Julia Hoefele
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- *Correspondence: Julia Hoefele
| |
Collapse
|
|
4
|
Arabi Z, Hamad A, Bukhari M, Altheaby A, Kaysi S. Practice Patterns for the Acceptance of Medically Complex Living Kidney Donors with Hematuria, Sickle Cell Trait, Smoking, Illegal Drug Use, or Urological Issues: A Multinational Survey. Avicenna J Med 2021; 11:185-195. [PMID: 34881201 PMCID: PMC8648410 DOI: 10.1055/s-0041-1736542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Background To review the practice patterns for the acceptance of medically complex living kidney donors (MCLKD) among the transplant providers of the international transplant community. Methods We distributed a survey globally, through major international transplantation societies, among nephrologists and transplant surgeons (TS). The survey contained questions regarding potential donors with microscopic hematuria, sickle cell trait, renal cysts, kidney stones, smoking, or illegal drug use. Results There were 239 respondents from 29 countries, including nephrologists (42%) and TS (58%). Although most respondents would investigate microscopic hematuria, one-third of them indicated they would decline these potential donors without investigation. Interestingly, most respondents accepted heavy smokers, intermittent illegal drug users (with advice to quit), and those with incidentally identified kidney stones, remote history of renal colic or simple renal cysts. We found multiple areas of consensus in practice with some interesting differences between nephrologists and TS. Conclusions This survey highlights the practice patterns of the acceptance of MCLKDs among the international community. In the absence of clear guidelines, this survey provides additional information to counsel kidney donors with microscopic hematuria, sickle cell trait, renal cysts, kidney stones, heavy smoking, or illegal drug use.
Collapse
Affiliation(s)
- Ziad Arabi
- Department of the Organ Transplant Center, Division of Adult Transplant Nephrology, King Abdulaziz Medical City, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Abdullah Hamad
- Department of Medicine, Division of Nephrology, Regional Medical Center of Orangeburg and Calhoun Counties, Orangeburg, South Carolina, United Sates
| | - Muhammad Bukhari
- Department of Medicine, Division of Adult Nephrology, Taif University, Taif, Saudi Arabia
| | - Abdulrahman Altheaby
- Department of the Organ Transplant Center, Division of Adult Transplant Nephrology, King Abdulaziz Medical City, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Saleh Kaysi
- Department of Medicine, Division of Nephrology, CHU Clermont-Ferrand, France
| |
Collapse
|
|
5
|
|
|
6
|
Nozu K, Takaoka Y, Kai H, Takasato M, Yabuuchi K, Yamamura T, Horinouchi T, Sakakibara N, Ninchoji T, Nagano C, Iijima K. Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome. Kidney Res Clin Pract 2020; 39:402-413. [PMID: 33214343 PMCID: PMC7771000 DOI: 10.23876/j.krcp.20.111] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/06/2020] [Accepted: 08/08/2020] [Indexed: 12/18/2022] Open
Abstract
Alport syndrome (AS) is a progressive inherited kidney disease characterized by hearing loss and ocular abnormalities. There are three forms of AS depending on inheritance mode: X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, which encodes type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode type IV collagen α3 or α4 chain, respectively. In male XLAS or ARAS cases, end-stage kidney disease (ESKD) develops around a median age of 20 to 30 years old, while female XLAS or ADAS cases develop ESKD around a median age of 60 to 70 years old. The diagnosis of AS is dependent on either genetic or pathological findings. However, determining the pathogenicity of the variants detected by gene tests can be difficult. Recently, we applied the following molecular investigation tools to determine pathogenicity: 1) in silico and in vitro trimer formation assay of α345 chains to assess triple helix formation ability, 2) kidney organoids constructed from patients’ induced pluripotent stem cells to identify α5 chain expression on the glomerular basement membrane, and 3) in vitro splicing assay to detect aberrant splicing to determine the pathogenicity of variants. In this review article, we discuss the genetic background and novel assays for determining the pathogenicity of variants. We also discuss the current treatment approaches and introduce exon skipping therapy as one potential treatment option.
Collapse
Affiliation(s)
- Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yutaka Takaoka
- Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, Japan
| | - Hirofumi Kai
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Minoru Takasato
- Laboratory for Human Organogenesis, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.,Laboratory of Molecular Cell Biology and Development, Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Kensuke Yabuuchi
- Laboratory for Human Organogenesis, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Tomohiko Yamamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Nana Sakakibara
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takeshi Ninchoji
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - China Nagano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|