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COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Konstantinos Voskarides^*, Loukas Damianou, Vassos Neocleous, Ioanna Zouvani, Stalo Christodoulidou, Valsamakis Hadjiconstantinou, Kyriacos Ioannou^||, Yiannis Athanasiou^||, Charalampos Patsias^¶, Efstathios Alexopoulos^**, Alkis Pierides^||, Kyriacos Kyriacou and Constantinos Deltas^*,

^* Department of Biological Sciences, University of Cyprus, Cyprus Institute of Neurology and Genetics, and Departments of Histopathology and ^|| Nephrology, Nicosia General Hospital, Nicosia, Cyprus; Department of Nephrology, Evangelismos Hospital, Athens, Greece; ^¶ Department of Nephrology, Larnaca General Hospital, Larnaca, Cyprus; and ^** Department of Nephrology, Aristotle University of Thessalloniki, Greece

Correspondence: Prof. Constantinos Deltas, Department of Biological Sciences, University of Cyprus, Kallipoleos 75, 1678 Nicosia, Cyprus. Phone: 00-357-22-892882; Fax: 00-357-22-892881; E-mail: Deltas{at}ucy.ac.cy

Received for publication April 13, 2007. Accepted for publication July 2, 2007.

Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in 40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.

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J. Am. Soc. Nephrol. 2007 18: F3. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673