MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Kopp JB
PROVIDER: S-EPMC2827354 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.
| S-EPMC5338705 | biostudies-literature
Project description:Genetic variation at the MYH9 locus is linked to the high incidence of focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease among African Americans. To further define risk alleles with FSGS we performed a genome-wide association analysis using more than one million single-nucleotide polymorphisms in 56 African-American and 61 European-American patients with biopsy-confirmed FSGS. Results were compared to 1641 European Americans and 1800 African Americans as unselected controls. While no association was observed in the cohort of European Americans, the case-control comparison of African Americans found variants within a 60 kb region of chromosome 22 containing part of the APOL1 and MYH9 genes associated with increased risk of FSGS. This region spans different linkage disequilibrium blocks, and variants associating with disease within this region are in linkage disequilibrium with variants which have shown signals of natural selection. APOL1 is a strong candidate for a gene that has undergone recent natural selection and is known to be involved in the infection by Trypanosoma brucei, a parasite common in Africa that has recently adapted to infect human hosts. Further studies will be required to establish which variants are causally related to kidney disease, what mutations caused the selective sweep, and to ultimately determine if these are the same.
| S-EPMC3001190 | biostudies-literature
Project description:Familial clustering of disparate kidney diseases including clinically diagnosed hypertensive and diabetic nephropathy, idiopathic focal segmental glomerulosclerosis, and HIV-associated nephropathy are often observed in African Americans. Admixture mapping recently identified the nonmuscle myosin heavy chain 9 gene (MYH9) as a susceptibility factor strongly associated with several nondiabetic etiologies of end-stage renal disease in African Americans, less strongly with diabetes-associated end-stage renal disease. MYH9-associated nephropathies reside in the spectrum of focal segmental glomerulosclerosis/focal global glomerulosclerosis. The renal histology in proteinuric African Americans homozygous for MYH9 risk variants with longstanding type 2 diabetes mellitus is unknown. We report a case of coincident idiopathic focal segmental glomerulosclerosis collapsing variant and diabetic nephropathy in an African American homozygous for the MYH9 E1 risk haplotype. This case demonstrates that diabetic African Americans with overt proteinuria can have mixed renal lesions, including those in the spectrum of MYH9-associated nephropathy. Careful interpretation of kidney biopsies in proteinuric African Americans with diabetes is necessary to exclude coincident nondiabetic forms of nephropathy, precisely define etiologies of kidney disease, and determine the natural history and treatment response in mixed lesions of diabetes-associated and MYH9-associated kidney disease.
| S-EPMC3022108 | biostudies-literature
Project description:Focal segmental glomerulosclerosis (FSGS) is a major cause of idiopathic steroid-resistant nephrotic syndrome (SRNS) and end-stage kidney disease (ESKD). In recent years, animal models and studies of familial forms of nephrotic syndrome helped elucidate some mechanisms of podocyte injury and disease progression in FSGS. This article reviews some of the experimental and clinical data on the pathophysiology of FSGS.
| S-EPMC1794138 | biostudies-other
Project description:The recent advances in understanding the pathophysiology of focal segmental glomerulosclerosis (FSGS) and molecular function of glomerular filtration barrier come directly from genetic linkage and positional cloning studies. The exact role and function of the newly discovered genes and proteins are being investigated by in vitro and in vivo mechanistic studies. Those genes and proteins interactions seem to change susceptibility to kidney disease progression. Better understanding of their exact role in the development of FSGS may influence future therapies and outcomes in this complex disease.
| S-EPMC2467504 | biostudies-literature
Project description:Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury observed either as an idiopathic finding or as a consequence of underlying systemic conditions. Several genes have been identified that, when mutated, lead to inherited FSGS and/or the related nephrotic syndrome. These findings have accelerated the understanding of glomerular podocyte function and disease, motivating our search for additional FSGS genes. Using linkage analysis, we identified a locus for autosomal-dominant FSGS susceptibility on a region of chromosome 14q. By sequencing multiple genes in this region, we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.
| S-EPMC2980844 | biostudies-literature
Project description:Until recently, knowledge of genetic causes of glomerular disease was limited to certain rare or uncommon inherited diseases, and to genes, either rare or with small effect, identified in candidate gene studies. These genetic factors accounted for only a very small fraction of kidney disease. However, the striking differences in frequency of many forms of kidney disease between African Americans and European Americans, which could not be explained completely by cultural or economic factors, pointed to a large unidentified genetic influence. Because focal segmental glomerulosclerosis (FSGS) and human immunodeficiency virus-associated collapsing glomerulopathy have striking racial disparities, we performed an admixture mapping study to identify contributing genetic factors. Admixture mapping identified genetic variants in the nonmuscle myosin heavy chain 9 gene (MYH9) as having a major influence on both FSGS and human immunodeficiency virus-associated collapsing glomerulopathy, with odds ratios from 4 to 8 and attributable fractions of 70% to 100%. Previously identified, rare, inherited MYH9 disorders point to a mechanism by which MYH9 variation disrupts the actin-myosin filaments responsible for maintaining the structure of podocytes, the cells that provide one of three filtration barriers in the glomeruli. MYH9 variation has a smaller but still highly significant effect on nondiabetic kidney disease, and a weaker but significant effect on diabetic kidney disease; it is unclear whether underlying cryptic FSGS is responsible for the MYH9 association with these diseases. The strong predicted power of MYH9 variation for disease indicates a clear role for genetic testing for these variants in personalized medicine, for assessment of genetic risk, and potentially for diagnosis.
| S-EPMC2862292 | biostudies-literature
Project description:The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif-containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLC?1, the identification of mutations that may alter the putative INF2-IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS.
| S-EPMC3029896 | biostudies-literature
Project description:Focal segmental glomerulosclerosis (FSGS) involves considerable histological heterogeneity in terms of location and quality of the glomerular segmental lesions. The present study investigated the heterogeneity of segmental lesions in each variant of FSGS, determined by the Columbia classification, and its clinical relevance. All glomerular segmental lesions of 80 cases of primary FSGS were evaluated histologically based on location [tip (TIP), perihilar (PH), or not otherwise specified (NOS)], and quality (cellular or fibrous). Among the 1,299 glomeruli of the 80 biopsy specimens, 210 glomeruli (16.2%) had segmental lesions, comprising 57 (27%) cellular TIP, 4 (2%) fibrous TIP, 42 (20%) cellular NOS, 86 (41%) fibrous NOS, and 21 (10%) fibrous PH lesions. Each case was also classified into one of the five histological variants of the Columbia classification: collapsing (COL), TIP, cellular (CEL), PH, or NOS. Overlap of segmental lesions in different location categories was seen in the COL, TIP, and PH variants, and heterogeneity of quality was apparent in the COL and CEL variants. Histological findings of the CEL variant (endocapillary hypercellularity) were observed in nine of the 13 COL variants. Both location and quality correlated with disease duration, degree of proteinuria, and histological severity of global glomerular sclerosis and tubulo-interstitial lesions. These results demonstrated the histological heterogeneity of glomerular segmental lesions in all variants of the Columbia classification, except NOS. However, the fidelity of location and dominance of histological features were generally conserved in the TIP and PH variants. The COL and CEL variants warrant further investigation because of their overlapping histological findings and apparent histological heterogeneity in the glomerular segmental lesions.
| S-EPMC3253997 | biostudies-literature
Project description:Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3' untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR = 4.9, P = 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR = 0.5, P = 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.
| S-EPMC4096868 | biostudies-literature