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MedRxiv : the Preprint Server For... Jun 2024Our knowledge of X-linked Alport Syndrome [AS] comes mostly from selected cohorts with more severe disease.
INTRODUCTION
Our knowledge of X-linked Alport Syndrome [AS] comes mostly from selected cohorts with more severe disease.
METHODS
We examined the phenotypic spectrum of X-linked AS in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health record data. Patients with variants reported as pathogenic (P) or likely pathogenic (LP) in ClinVar, or protein-truncating variants (PTVs), were each matched with up to 5 controls without variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. AS-related phenotypes included dipstick hematuria, bilateral sensorineural hearing loss (BSHL), proteinuria, decreased eGFR, and ESKD.
RESULTS
Out of 170,856 patients, there were 30 hemizygous males (mean age 52.4 [SD 19.8] years) and 56 heterozygous females (mean age 58.5 [SD 19.4]) with a P/LP variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any AS phenotypic feature) was highest for non-p.Gly624Asp P/LP variants (males: 89%, females: 86%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with ESKD was highest for males with P/LP variants (41%), intermediate for males with p.Gly624Asp (15%) and females with P/LP variants (10%), compared to controls (males: 3%, females 2%). Only 33% of males and 11% of females had a known diagnosis of Alport syndrome or thin basement membrane disease. Only 47% of individuals with had completed albuminuria screening, and a minority were taking renin-angiotensin aldosterone system (RAAS) inhibitors.
CONCLUSION
In an unselected cohort, we show increased risks of AS-related phenotypes in men and women compared to matched controls, while showing a wider spectrum of severity than has been described previously and variability by genotype. Future studies are needed to determine whether early genetic diagnosis can improve outcomes in Alport Syndrome.
PubMed: 38883771
DOI: 10.1101/2024.06.04.24308453 -
International Journal of Nephrology and... 2024X-linked Alport syndrome (XLAS) is caused by pathogenic variants in which lead to abnormalities of the glomerular basement membrane (GBM) structural and is...
INTRODUCTION
X-linked Alport syndrome (XLAS) is caused by pathogenic variants in which lead to abnormalities of the glomerular basement membrane (GBM) structural and is characterized by progressive kidney disease, hearing loss, and ocular abnormalities. The aim of this study was to identify gene mutations in a Chinese family with XLAS by whole-exome sequencing (WES) and verified the pathogenicity of the mutation in vitro experiments.
CASE PRESENTATION
A five-generation pedigree with a total of 49 family members originating from Hainan province of China was investigated in this study. The proband was a 23-year-old male who developed microscopic hematuria, proteinuria and end-stage kidney disease (ESKD) at age 17. WES identified a novel splicing mutation c.321+5G>A of , which cause exon skip. Further co-segregation analysis confirmed that this mutation exists in relatives who had renal abnormalities using Sanger sequencing. According to American College of Medical Genetics and Genomics guidelines (ACMG), the mutation was determined to be of uncertain significance (VUS). In vitro splicing experiments have shown that the variant induces aberrant mRNA splicing and transcript deletion.
CONCLUSION
We identified a novel intronic pathogenic mutation (c.321+5G>A) in a Chinese XLAS family and described the phenotypes of affected relatives. This study expands the mutation spectrum of gene in XLAS and demonstrates the importance of gene screening for AS.
PubMed: 38855711
DOI: 10.2147/IJNRD.S459363 -
Translational Pediatrics May 2024Alport syndrome (AS) is a rare progressive hereditary kidney disease that is clinically principally associated with hematuria, proteinuria, and progressive renal...
BACKGROUND
Alport syndrome (AS) is a rare progressive hereditary kidney disease that is clinically principally associated with hematuria, proteinuria, and progressive renal dysfunction. This condition not only impairs renal function but also potentially affects auditory and ocular health, significantly impacting the patient's quality of life.
CASE DESCRIPTION
This article reports a young girl with AS, combined with dwarfism attributable to growth hormone (GH) deficiency, diagnosed at Wenzhou People's Hospital in 2019. The clinical data and diagnostic steps were retrospectively analyzed. Genetic testing showed that she carried a new mutation in the gene, c.2317_2318delAG (p.R773Gfs*14), classified as "pathogenic" under the criteria of the American College of Medical Genetics and Genomics (ACMG), confirming her AS diagnosis. Significantly, the patient's height was more than two standard deviations (SDs) below the average for children of her race, sex, and age. The peak GH level post-stimulation was below 5 ng/mL, coupled with a growth rate of less than 5 cm/year, leading to the diagnosis of GH deficiency. Consequently, recombinant human GH (rhGH) therapy was initiated.
CONCLUSIONS
After a year of rhGH treatment, we observed a notable increase in her height, without any adverse effects like elevated intracranial pressure, hypothyroidism, or worsening kidney function.
PubMed: 38840691
DOI: 10.21037/tp-23-569 -
Frontiers in Genetics 2024Alport Syndrome (AS) is a genetic kidney disorder characterized by progressive hearing loss and atypical eye symptoms, resulting in a poor prognosis and lack of...
Alport Syndrome (AS) is a genetic kidney disorder characterized by progressive hearing loss and atypical eye symptoms, resulting in a poor prognosis and lack of effective targeted therapy. The primary mode of inheritance is X-linked dominant (XLAS) due to variants in the gene. This study revealed a previously unidentified alternative form of the gene, namely, the c.4822-10T>C variant, which was confirmed through experiments. To investigate the impact of a splicing variant on mRNA production, an minigene splicing assay was utilized. Additionally, molecular dynamics was employed to predict the ability of α5(IV) to form a triple helix. Results from the experiment revealed that the wild-type (WT) plasmid produced two distinct mRNA products simultaneously. Sequence analysis using the BLAST database revealed a 173-bp deletion in the mRNA sequence of the first product, indicating a potential similarity to the XM_016942897.2 transcript of . The second mRNA product of the WT plasmid contained the full sequence of exons 51, 52, and 53, as anticipated. Conversely, the mutant (MT) plasmid generated a single mRNA product with a 173-bp deletion in exon 52, leading to the identification of the mature mRNA expression as NM_033380.2: COL4A5: c.4822_4994del. In the context of nonsense-mediated mRNA decay (NMD), the deletion c.4822_4994 results in the production of a truncated protein, p.His1608*, that terminates prematurely. This truncated protein may disrupt the secondary structure of α5(IV) and potentially cause an abnormal conformation of α345(IV). This study examines the relationship between the variable splicing pattern in the NM_033380.2 transcript of the gene in XLAS patients and the presence of the gene splice variant c.4822-10T>C. Our findings indicate that the c.4822-10T>C splice variant leads to activation of nonsense-mediated mRNA degradation (NMD) and reduced mRNA expression, resulting in inadequate synthesis of the corresponding proteins. This aligns with the patient's immunofluorescence results showing negative α5(IV) chain presence at the glomerular basement membrane, bursa, and tubular basement membrane, confirming the pathogenic nature of c.4822-10T>C.
PubMed: 38818038
DOI: 10.3389/fgene.2024.1330525 -
Journal of Translational Internal... Apr 2024
PubMed: 38812923
DOI: 10.2478/jtim-2024-0005 -
Clinical Science (London, England :... Jun 2024Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This... (Review)
Review
Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT1 and ETA receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ETA and AT1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.
Topics: Humans; Animals; Renal Insufficiency, Chronic; Kidney; Endothelin A Receptor Antagonists; Angiotensin II Type 1 Receptor Blockers; Disease Models, Animal
PubMed: 38808486
DOI: 10.1042/CS20240249 -
Frontiers in Nephrology 2024Congenital nephrotic syndrome (CNS) is a severe kidney disorder characterized by edema, massive proteinuria, and hypoalbuminemia that manifests or within three months...
BACKGROUND
Congenital nephrotic syndrome (CNS) is a severe kidney disorder characterized by edema, massive proteinuria, and hypoalbuminemia that manifests or within three months after birth. CNS affects 1-3 per 100,000 children, primarily associated with genetic variants and occasionally with infections. Genetic analysis is the first-line method for diagnosis. The most common founder variants have been identified in European populations, often resulting in end-stage kidney disease by 1-2 years of age.
CASE-DIAGNOSIS/TREATMENT
A female full-term neonate, without prenatal signs of kidney disease, was admitted to Rapa Nui (Eastern Island) Hospital at the age of 2 months due to bronchial obstruction. She presented fever, oliguria, edema, urine protein-to-creatinine ratio (UPCR) 433.33, and hypoalbuminemia (0.9 g/dL). She was transferred to a mainland Chilean hospital following CNS diagnosis. Viral screening detected cytomegalovirus (CMV) positivity in both blood and urine. A kidney biopsy revealed interstitial nephritis and diffuse podocyte damage and the tissue PCR resulted negative for CMV. Interviews with the parents revealed consanguinity, suggestive of hereditary CNS. Genetic analysis identified the Maori founder variant, c.2131C>A (p.R711S), in homozygosis. The patient received albumin infusions and antiviral therapy, being discharged when she was 5 months old, with improved laboratory parameters evidenced by UPCR 28.55, albumin 2.5 g/dL, and cholesterol 190 mg/dL. Subsequent clinical monitoring was conducted through virtual and in-person consultations. At her last follow-up at 4 years 2 months old, she presented UPCR 16.1, albumin 3.3 g/dl and cholesterol 220 mg/dL, maintaining normal kidney function and adequate growth.
CONCLUSIONS
To our knowledge, this represents the first case of CNS in Chile carrying a variant associated with prolonged kidney survival. As described in the Maori population, the patient exhibited a less severe clinical course compared to classical patients. Genetic testing for the Maori founder variant in CNS patients related to the New Zealand population, could impact management decisions and potentially prevent the need for nephrectomies.
PubMed: 38808020
DOI: 10.3389/fneph.2024.1379061 -
Genes May 2024Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by , , and pathogenic variants. The classic phenotypic spectrum associated with AS...
Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by , , and pathogenic variants. The classic phenotypic spectrum associated with AS ranges from isolated hematuria to chronic kidney disease (CKD) with extrarenal abnormalities. Atypical presentation of the disorder is possible, and it can mislead the diagnosis. Polycystic kidney disease (PKD), which is most frequently associated with Autosomal Dominant PKD (ADPKD) due to and heterozygous variants, is emerging as a possible clinical manifestation in patients. We describe a novel familial frameshift variant (NM_000495.5: c.1095dup p.(Leu366ValfsTer45)), which was associated with AS and PKD in the hemizygous proband, as well as with PKD, IgA glomerulonephritis and focal segmental glomerulosclerosis (FSGS) in the heterozygous mother. Establishing the diagnosis of AS can sometimes be difficult, especially in the context of misleading family history and atypical phenotypic features. This case study supports the emerging genotypic and phenotypic heterogeneity in -associated disorders, as well as the recently described association between PKD and collagen type IV (Col4) defects. We highlight the importance of the accurate phenotyping of all family members and the relevance of next-generation sequencing in the differential diagnosis of hereditary kidney disease.
Topics: Humans; Nephritis, Hereditary; Collagen Type IV; Male; Female; Pedigree; Adult; Polycystic Kidney Diseases; Frameshift Mutation; Phenotype; Polycystic Kidney, Autosomal Dominant
PubMed: 38790225
DOI: 10.3390/genes15050597 -
Genes May 2024Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD).
BACKGROUND
Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD).
METHODS
This is a single-center, retrospective study that included 36 adults with type IV collagen (COL4) mutations. Our main scope was to describe how genetic features influence renal survival.
RESULTS
A total of 24 different mutations were identified, of which eight had not been previously described. Mutations affecting each of the type IV collagen α chains were equally prevalent (33.3%). Most of the patients had pathogenic variants (61.1%). Most patients had a family history of kidney disease (71%). The most prevalent clinical picture was nephritic syndrome (64%). One-third of the subjects had extrarenal manifestations, 41.6% of patients had ESKD at referral, and another 8.3% developed ESKD during follow-up. The median renal survival was 42 years (95% CI, 29.98-54.01). The COL4A4 group displayed better renal survival than the COL4A3 group ( = 0.027). Patients with missense variants had higher renal survival ( = 0.023). Hearing loss was associated with lower renal survival ( < 0.001).
CONCLUSIONS
Patients with COL4A4 variants and those with missense mutations had significantly better renal survival, whereas those with COL4A3 variants and those with hearing loss had worse prognoses.
Topics: Humans; Nephritis, Hereditary; Female; Male; Collagen Type IV; Adult; Middle Aged; Genetic Association Studies; Kidney Failure, Chronic; Mutation; Retrospective Studies; Autoantigens
PubMed: 38790222
DOI: 10.3390/genes15050593 -
Kidney International May 2024COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains...
COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.
PubMed: 38782199
DOI: 10.1016/j.kint.2024.04.015