Abstract
Familial hematuria (FH) is explained by at least four different genes (see below). About 50% of patients develop late proteinuria and chronic kidney disease (CKD). We hypothesized that MYH9/APOL1, two closely linked genes associated with CKD, may be associated with adverse progression in FH. Our study included 102 thin basement membrane nephropathy (TBMN) patients with three known COL4A3/COL4A4 mutations (cohort A), 83 CFHR5/C3 glomerulopathy patients (cohort B) with a single CFHR5 mutation and 15 Alport syndrome patients (cohort C) with two known COL4A5 mild mutations, who were categorized as “Mild” (controls) or “Severe” (cases), based on renal manifestations. E1 and S1 MYH9 haplotypes and variant rs11089788 were analyzed for association with disease phenotype. Evidence for association with “Severe” progression in CFHR5 nephropathy was found with MYH9 variant rs11089788 and was confirmed in an independent FH cohort, D (cumulative p value = 0.001, odds ratio = 3.06, recessive model). No association was found with APOL1 gene. Quantitative Real time PCR did not reveal any functional significance for the rs11089788 risk allele. Our results derive additional evidence supporting previous reports according to which MYH9 is an important gene per se, predisposing to CKD, suggesting its usefulness as a prognostic marker for young hematuric patients.
Highlights
The differential diagnosis in 2012 for familial hematuria (FH) includes mostly the COL4A3/A4 heterozygous carriers that exhibit thin basement membrane nephropathy (TBMN) with lifelong microscopic hematuria [1,2,3,4,5] and a newly described disease, CFHR5 nephropathy, with isolated C3 mesangial deposits [6,7]
Our results demonstrate a likely contribution of MYH9 variant rs11089788 in the progression of chronic kidney disease (CKD) when co-inherited with CFHR5 nephropathy, but cast doubt on the recently alleged association with variation in the APOL1 gene that is closely linked to MYH9
None of the analyzed MYH9 SNPs was significantly associated with phenotypes in any of our initial cohorts
Summary
The differential diagnosis in 2012 for familial hematuria (FH) includes mostly the COL4A3/A4 heterozygous carriers that exhibit thin basement membrane nephropathy (TBMN) with lifelong microscopic hematuria [1,2,3,4,5] and a newly described disease, CFHR5 nephropathy, with isolated C3 mesangial deposits [6,7]. CFHR5 nephropathy is an autosomal dominant disease with an up to now unknown prevalence, it is highly prevalent in Cyprus [6,7]. X-linked Alport syndrome cases (male patients) with mild mutations in the COL4A5 gene, often present as phenocopies of TBMN, with a wide spectrum of phenotypes [11,12,13,14,15,16,17]. We hypothesize that this great phenotypic heterogeneity is largely due to modifier genes [10]
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