COL4A3/COL4A4 heterozygous mutations with TBMN presenting as focal segmental glomerulosclerosis
Authors: Constantinos Deltas, Alkis Pierides
Journal: Kidney International (2015)

To the Editor: In previous years, several authors reported on thin basement membrane nephropathy (TBMN), also then known as benign familial microscopic hematuria (MH), which was occasionally accompanied by proteinuria and chronic renal failure (CRF) in the presence of focal segmental glomerulosclerosis (FSGS)1.Gregory M.C. The clinical features of thin basement membrane nephropathy.Semin Nephrol. 2005; 25: 140-145Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,2.Savige J. Rana K. Tonna S. et al.Thin basement membrane nephropathy.Kidney Int. 2003; 64: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar (and references there in). Those publications were not supported by molecular studies. Starting from the late 1980s and during the next decade we identified in Cyprus several large families with hereditary autosomal dominant FSGS and several members showing progressive CRF. In 2002, we initiated a genetic study, looking for the then known familial FSGS genes (ACTN4, CD2AP, and TRPC6) but no linkage was found. The clinical symptoms included lifelong MH, proteinuria, and CRF of variable degrees. After failing to detect mutations in the above genes, we turned to collagen IV and very quickly identified three heterozygous mutations in the COL4A3/A4 genes. In 2007 we published on a large cohort of 82 patients, belonging to 10 of 13 Greek–Cypriot families with autosomal dominant FSGS.3.Voskarides K. Damianou L. Neocleous V. et al.COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy.J Am Soc Nephrol. 2007; 18: 3004-3016Crossref PubMed Scopus (160) Google Scholar Subsequently, we expanded this work to nearly 250 patients in 30 families with pathogenic COL4A3/A4 mutations, 35% of whom reached end-stage kidney disease (ESKD) by age 70 years.4.Pierides A. Voskarides K. Athanasiou Y. et al.Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2009; 24: 2721-2729Crossref PubMed Scopus (100) Google Scholar, 5.Deltas C. Pierides A. Voskarides K. Molecular genetics of familial hematuric diseases.Nephrol Dial Transplant. 2013; 28: 2946-2960Crossref PubMed Scopus (65) Google Scholar, 6.Papazachariou L. Demosthenous P. Pieri M. et al.Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing.PloS one. 2014; 9: e115015Crossref PubMed Scopus (46) Google Scholar The histological findings on all 26 renal biopsies from 17 families featured FSGS with podocyte foot process effacement and thin membranes, thus justifying the dual diagnosis of TBMN and FSGS. These data have been presented in several international conferences including the ERA-EDTA of 2012 and 2013 and the recent ASN (Deltas C. AR-Alport presenting as FSGS. ASN Kidney Week 11–16 November 2014. Philadelphia, PA, USA). We read with interest and surprise the recent publication by Malone et al.,7.Malone A.F. Phelan P.J. Hall G. et al.Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.Kidney Int. 2014; 86: 1253-1259Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar who found similar heterozygous collagen IV mutations in 6 of 70 families segregating familial FSGS. These authors have elected to totally ignore all previous extensive publications on a much larger series of similar patients and they appear to claim an original observation, which is totally unfair. We view their paper as a confirmation of our findings, indicating once again that heterozygous COL4A3/A4 mutations may not always maintain normal kidney function. It is our experience that in nearly all large pedigrees at least one patient will have developed severe CRF/ESKD usually after the age of 40 years (mean age at ESKD 57.4 years). In addition, these findings widen the spectrum of collagen IV nephropathies to include benign familial MH, TBMN, FSGS, and the Alport Syndrome. Next-generation sequencing technologies that allow whole-exome sequencing will unravel many more similar cases, allowing earlier diagnoses and correct treatment.