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International Journal of Molecular... Mar 2023Alport syndrome (AS) is a hereditary kidney disease caused by pathogenic variants in and genes with autosomal recessive or autosomal dominant transmission or in the... (Review)
Review
Alport syndrome (AS) is a hereditary kidney disease caused by pathogenic variants in and genes with autosomal recessive or autosomal dominant transmission or in the gene with X-linked inheritance. Digenic inheritance was also described. Clinically it is associated with microscopic hematuria, followed by proteinuria and chronic renal insufficiency with end-stage renal disease in young adults. Nowadays, there is no curative treatment available. The inhibitors of RAS (renin-angiotensin system) since childhood slow the progression of the disease. Sodium-glucose cotransporter-2 inhibitors seem to be promising drugs from DAPA-CKD (dapagliflozin-chronic kidney disease) study, but only a limited number of patients with Alport syndrome was included. Endothelin type A receptor and angiotensin II type 1 receptor combined inhibitors, and lipid-lowering agents are used in ongoing studies in patients with AS and focal segmental glomerulosclerosis (FSGS). Hydroxychloroquine in AS is studied in a clinical trial in China. Molecular genetic diagnosis of AS is crucial not only for prognosis prediction but also for future therapeutic options. Different types of mutations will require various types of gene, RNA, or protein therapy to improve the function, the of final protein product.
Topics: Child; Humans; Young Adult; Autoantigens; Collagen Type IV; Hematuria; Mutation; Nephritis, Hereditary; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36982595
DOI: 10.3390/ijms24065522 -
Kidney360 Dec 2021
Topics: Collagen Type IV; Female; Humans; Laminin; Male; Nephritis, Hereditary
PubMed: 35419542
DOI: 10.34067/KID.0007312021 -
Matrix Biology : Journal of the... Oct 2018The glomerular basement membrane (GBM) is an important component of the kidney's glomerular filtration barrier. Like all basement membranes, the GBM contains type IV... (Review)
Review
The glomerular basement membrane (GBM) is an important component of the kidney's glomerular filtration barrier. Like all basement membranes, the GBM contains type IV collagen, laminin, nidogen, and heparan sulfate proteoglycan. It is flanked by the podocytes and glomerular endothelial cells that both synthesize it and adhere to it. Mutations that affect the GBM's collagen α3α4α5(IV) components cause Alport syndrome (kidney disease with variable ear and eye defects) and its variants, including thin basement membrane nephropathy. Mutations in LAMB2 that impact the synthesis or function of laminin α5β2γ1 (LM-521) cause Pierson syndrome (congenital nephrotic syndrome with eye and neurological defects) and its less severe variants, including isolated congenital nephrotic syndrome. The very different types of kidney diseases that result from mutations in collagen IV vs. laminin are likely due to very different pathogenic mechanisms. A better understanding of these mechanisms should lead to targeted therapeutic approaches that can help people with these rare but important diseases.
Topics: Abnormalities, Multiple; Collagen Type IV; Eye Abnormalities; Glomerular Basement Membrane; Humans; Laminin; Mutation; Myasthenic Syndromes, Congenital; Nephritis, Hereditary; Nephrotic Syndrome; Pupil Disorders
PubMed: 29673759
DOI: 10.1016/j.matbio.2018.04.008 -
Current Opinion in Nephrology and... May 2024With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans,... (Review)
Review
PURPOSE OF REVIEW
With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype-phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes "classic" Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called "Alport kidney diseases".
RECENT FINDINGS
Several research studies have focused on the genotype-phenotype correlation under the latest classification scheme of AS. The historic diagnoses of "benign familial hematuria" and "thin basement membrane nephropathy" linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression.
SUMMARY
The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.
Topics: Humans; Nephritis, Hereditary; Hematuria; Kidney; Collagen Type IV; Mutation
PubMed: 38477333
DOI: 10.1097/MNH.0000000000000983 -
European Journal of Human Genetics :... May 2022In 1927 Arthur Cecil Alport, a South African physician, described a British family with an inherited form of kidney disease that affected males more severely than...
In 1927 Arthur Cecil Alport, a South African physician, described a British family with an inherited form of kidney disease that affected males more severely than females and was sometimes associated with hearing loss. In 1961, the eponymous name Alport syndrome was adopted. In the late twentieth century three genes responsible for the disease were discovered: , , and encoding for the α3, α4, α5 polypeptide chains of type IV collagen, respectively. These chains assemble to form heterotrimers of type IV collagen in the glomerular basement membrane. Scientists, clinicians, patient representatives and their families, and pharma companies attended the 2019 International Workshop on Alport Syndrome, held in Siena, Italy, from October 22 to 26, and the 2021 online Workshop from November 30 to December 4. The main topics included: disease re-naming, acknowledging the need to identify an appropriate term able to reflect considerable clinical variability; a strategy for increasing the molecular diagnostic rate; genotype-phenotype correlation from monogenic to digenic forms; new therapeutics and new therapeutic approaches; and gene therapy using gene editing. The exceptional collaborative climate that was established in the magical medieval setting of Siena continued in the online workshop of 2021. Conditions were established for collaborations between leading experts in the sector, including patients and drug companies, with the aim of identifying a cure for Alport syndrome.
Topics: Collagen Type IV; Female; Humans; Male; Nephritis, Hereditary
PubMed: 35260866
DOI: 10.1038/s41431-022-01075-0 -
Kidney International Nov 1996
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American Journal of Medical Genetics.... Sep 2022Alport syndrome is an inherited disorder of the kidneys that results from variants in three collagen IV genes-COL4A3, COL4A4, and COL4A5. Early diagnosis and... (Review)
Review
Alport syndrome is an inherited disorder of the kidneys that results from variants in three collagen IV genes-COL4A3, COL4A4, and COL4A5. Early diagnosis and pharmacologic intervention can delay the progression of chronic kidney disease and the onset of kidney failure in patients with Alport syndrome. This article describes the evolution of approaches to the diagnosis and early treatment of Alport syndrome.
Topics: Humans; Nephritis, Hereditary; Hematuria; Nephrologists; Collagen Type IV; Genetic Testing; Mutation
PubMed: 35775584
DOI: 10.1002/ajmg.c.31987 -
Kidney International Aug 2018Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing...
Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing genes. Here we develop a comprehensive approach for genetic diagnosis of inherited cystic and glomerular nephropathies. Targeted next generation sequencing of 140 genes causative of or associated with cystic or glomerular nephropathies was performed in 421 patients, a validation cohort of 116 patients with previously known mutations, and a diagnostic cohort of 207 patients with suspected inherited cystic disease and 98 patients with glomerular disease. In the validation cohort, a sensitivity of 99% was achieved. In the diagnostic cohort, causative mutations were found in 78% of patients with cystic disease and 62% of patients with glomerular disease, mostly familial cases, including copy number variants. Results depict the distribution of different cystic and glomerular inherited diseases showing the most likely diagnosis according to perinatal, pediatric and adult disease onset. Of all the genetically diagnosed patients, 15% were referred with an unspecified clinical diagnosis and in 2% genetic testing changed the clinical diagnosis. Therefore, in 17% of cases our genetic analysis was crucial to establish the correct diagnosis. Complex inheritance patterns in autosomal dominant polycystic kidney disease and Alport syndrome were suspected in seven and six patients, respectively. Thus, our kidney-disease gene panel is a comprehensive, noninvasive, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited kidney diseases. This allows etiologic diagnosis in three-quarters of patients and is especially valuable in patients with unspecific or atypical phenotypes.
Topics: Adolescent; Adult; Age of Onset; Aged; Child; Child, Preschool; Cohort Studies; Cost-Benefit Analysis; DNA Mutational Analysis; Feasibility Studies; Female; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Kidney; Male; Middle Aged; Mutation; Nephritis, Hereditary; Phenotype; Polycystic Kidney, Autosomal Dominant; Pregnancy; Prenatal Diagnosis; Prevalence; Young Adult
PubMed: 29801666
DOI: 10.1016/j.kint.2018.02.027 -
Translational Vision Science &... Mar 2022To analyze the characteristics of the choriocapillaris and the choroid in patients with Alport syndrome (AS) and investigate their clinical and demographic associations.
PURPOSE
To analyze the characteristics of the choriocapillaris and the choroid in patients with Alport syndrome (AS) and investigate their clinical and demographic associations.
METHODS
Multicenter, cross-sectional study. Forty-two eyes with AS were consecutively enrolled. A cohort of 33 healthy eyes was included as controls. Demographics and medical history were collected for each participant. Each eye underwent 3 × 3 swept-source optical coherence tomography angiography (PLEX Elite 9000 2.0; Carl Zeiss Meditec, Dublin, CA, USA) and spectral-domain OCT (Spectralis HRA2; Heidelberg Engineering, Heidelberg, Germany). Choriocapillaris flow deficit (FD) number, mean FD size, total FD area, FD density, subfoveal choroidal thickness (CT), total CT, and choroidal vascularity index (CVI) were compared between AS and control eyes. Factors associated with the FD density and the CVI in AS were explored with multivariable linear mixed models.
RESULTS
There was high intragroup variability in choriocapillaris and choroidal measurements in patients with AS. Choriocapillaris FD in patients with AS were more numerous compared to controls (P = 0.02). FD density in eyes with AS increased with older age (estimate = 0.31% for each year; 95% confidence interval [CI], 0.06-0.57; P = 0.02) and was higher in patients with a history of kidney transplant (estimate = 9.66% in case of positive history; 95% CI, 3.52-15.8; P = 0.006). The CVI was lower in eyes with dot maculopathy (estimate = -3.30% if present; 95% CI, -6.38 to -0.21; P = 0.04) and anterior lenticonus (estimate = -6.50% if present; 95% CI, -10.99 to -2.00; P = 0.006).
CONCLUSIONS
Patients with AS with kidney involvement requiring transplant may present with more severe choriocapillaris impairment. Lower choroidal vascularity was found in the presence of other ocular structural abnormalities.
TRANSLATIONAL RELEVANCE
An increased load of choriocapillaris flow deficits on optical coherence tomography angiography was found in patients with Alport syndrome who also had severe kidney disease requiring transplant.
Topics: Choroid; Cross-Sectional Studies; Female; Humans; Macular Degeneration; Male; Nephritis, Hereditary; Tomography, Optical Coherence
PubMed: 35311929
DOI: 10.1167/tvst.11.3.23 -
Current Opinion in Nephrology and... May 2022In Alport syndrome, over 1,700 genetic variants in the COL4A3, COL4A4, and COL4A5 genes cause the absence or malfunctioning of the collagen IVα345 scaffold - an... (Review)
Review
PURPOSE OF REVIEW
In Alport syndrome, over 1,700 genetic variants in the COL4A3, COL4A4, and COL4A5 genes cause the absence or malfunctioning of the collagen IVα345 scaffold - an essential component of the glomerular basement membrane (GBM). Therapies are limited to treatment with Angiotensin-Converting enzyme (ACE) inhibitors to slow progression of the disease. Here, we review recent progress in therapy development to replace the scaffold or restore its function.
RECENT FINDINGS
Multiple approaches emerged recently for development of therapies that target different stages of production and assembly of the collagen IVα345 scaffold in the GBM. These approaches are based on (1) recent advances in technologies allowing to decipher pathogenic mechanisms that underlie scaffold assembly and dysfunction, (2) development of DNA editing tools for gene therapy, (3) RNA splicing interference, and (4) control of mRNA translation.
SUMMARY
There is a growing confidence that these approaches will ultimately provide cure for Alport patients. The development of therapy will be accelerated by studies that provide a deeper understanding of mechanisms that underlie folding, assembly, and function of the collagen IVα345 scaffold.
Topics: Collagen Type IV; Female; Glomerular Basement Membrane; Humans; Male; Nephritis, Hereditary; Prospective Studies
PubMed: 35283436
DOI: 10.1097/MNH.0000000000000789