Abstract
BackgroundMutations in INF2 are frequently responsible for focal segmental glomerulosclerosis (FSGS), which is a common cause of end stage renal disease (ESRD); additionally, they are also connected with Charcot-Marie-Tooth neuropathy. INF2 encodes for inverted formin 2. This protein participates in regulation of the dynamics of the actin cytoskeleton, involving not only the polymerisation, but also the depolymerisation of filaments. The present study is the first mutational analysis of INF2 done in the Czech Republic.MethodsMutational analysis of INF2 was performed on 109 patients (mean age at onset 41.44 ± 18.91 years) with FSGS or minimal change disease (MCD); and also in 6 patients without renal biopsy who had already developed chronic kidney disease (CKD)/ESRD at the time of diagnosis. We used high resolution melting method (HRM), with subsequent Sanger sequencing, in suspect samples from HRM analysis. The HRM method is an effective method for the screening of large cohorts of patients.ResultsTwo pathogenic mutations (p.Arg214His and p.Arg218Gln) were detected in INF2. The first (p.Arg214His) was identified in the FSGS patient with a positive family history. The second mutation (p.Arg218Gln) was found in two brothers with ESRD of unknown etiology. The most frequent sequence change was the substitution p.P35P, the incidence of which corresponded with the frequencies available in the ExAC Browser and gnomAD Browser databases. This analysis also detected different exonic and intronic changes that probably did not influence the phenotype of the included patients.ConclusionsThe INF2 mutational screening is useful in familial FSGS cases as well as in patients with an unknown cause for their ESRD, but with a positive family history. INF2 seems to be not only the cause of FSGS, but also of ESRD of unknown etiology. Our study has confirmed that the HRM analysis is a very useful method for the identification of single nucleotide substitutions.
Highlights
Mutations in Inverted formin 2 (INF2) are frequently responsible for focal segmental glomerulosclerosis (FSGS), which is a common cause of end stage renal disease (ESRD); they are connected with Charcot-Marie-Tooth neuropathy
We present a mutational analysis of INF2 in patients with FSGS or Minimal change disease (MCD) as well as in a group of patients with a positive family history of ESRD
INF2 mutational analysis was performed in a total of the 115 patients with FSGS (77 patients) /MCD (32 patients), or the characteristics of a separate group including a positive family history for ESRD in combination with developed advanced chronic kidney disease (CKD)/ESRD at the time of diagnosis
Summary
Mutations in INF2 are frequently responsible for focal segmental glomerulosclerosis (FSGS), which is a common cause of end stage renal disease (ESRD); they are connected with Charcot-Marie-Tooth neuropathy. Podocytes are highly specialized cells with a unique and highly differentiated cytoarchitecture Their main functions include: support of the glomerular capillaries, synthesis of glomerular basement membrane (GBM), and regulation of permselectivity. We still have only limited insight into the pathogenesis of both MCD and FSGS Both the etiology and histology of FSGS as well as of MCD may be very variable, including: viral infections, toxic agents, adaptive structural-functional responses, and mutations in the genes encoding proteins specific for podocytes (or highly expressed in them) [1,2,3], such as: ACTN4 [4], INF2 [5], and TRPC6 [6]
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