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Possible Digenic Disease in a Caucasian Family with COL4A3 and COL4A5 Mutations
Mira Choi1,2, Yoland-Marie Anistan3,4, Kai-Uwe Eckardt3
1Department of Nephrology and Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany, mira.choi@charite.de.
Insights
Alport syndrome, a kidney disease, can result from mutations in collagen IV genes. This study identifies a new digenic inheritance pattern involving COL4A3 and COL4A5 mutations, expanding our understanding of familial nephropathy.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Alport syndrome is a hereditary kidney disease caused by mutations in collagen IV genes (COL4A3, COL4A4, COL4A5), affecting the glomerular basement membrane.
- Microscopic hematuria is a common early symptom, but progression to proteinuria and end-stage renal disease can occur even in mild cases.
Observation:
- Recent studies suggest digenic inheritance (mutations in two different genes) can cause Alport syndrome.
- A Caucasian family presented with simultaneous mutations in COL4A3 and COL4A5.
Findings:
- A novel mutation in COL4A3 (c.4484A>G, p.Gln1495Arg) and a known mutation in COL4A5 (c.1871G>A, p.Gly624Asp) were identified in the family.
- Segregation analysis supports a digenic inheritance pattern for Alport syndrome involving COL4A3 and COL4A5 mutations.
Implications:
- This finding expands the known genetic mechanisms of Alport syndrome.
- Understanding digenic inheritance patterns is crucial for accurate diagnosis and genetic counseling in familial nephropathies.
Abstract:
Microscopic hematuria is a common feature of patients with Alport syndrome, a familial nephropathy due to mutations in COL4A3, COL4A4 or COL4A5. These genes encode for α3, α4, and α5 type IV collagen polypeptide chains (collagen IV α345), crucial for the structural component of the glomerular basement membrane. Even patients with mild phenotype, namely isolated microhematuria (X-linked females with thin basement membrane on electron microscopy or heterozygous carriers of COL4A3 or COL4A4 mutations), can potentially progress to proteinuria and to end-stage renal disease. Recent pedigree analyses provided evidence for digenic inheritance of Alport syndrome by concomitant mutations in COL4A3/COL4A4 or COL4A4/COL4A5. We describe a Caucasian family with concomitant COL4A3 and COL4A5 mutations, consisting of a novel c.4484A>G COL4A3 (p.Gln1495Arg) mutation and a previously reported c.1871G>A COL4A5 (p.Gly624Asp) mutation. Our segregation analysis raises the possibility that Alport syndrome resembles also digenic inheritance by COL4A3/COL4A5.
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