TY - JOUR
T1 - Molecular genetics of familial hematuric diseases
AU - Deltas, Constantinos
AU - Pierides, Alkis
AU - Voskarides, Konstantinos
N1 - Funding Information:
The authors express their gratitude to all patients and relatives who participated in the work performed at the Molecular Medicine Research Center and is presented in this review publication. We also thank the many clinicians who recruited patients for the work presented as part of this review and that was firstly described in other original publications. The work was partly supported from the Cyprus Research Promotion Foundation, through the grants ΠENEK/ENIΣX/0505/ 02, ΠENEK/ENIΣX/0308/08 and a grant co-funded by the European Regional Development Fund and the Republic of Cyprus through the Research Promotion Foundation (Strategic Infrastructure Project NEW INFRASTRUCTURE/STRATEGIC/ 0308/24 to C.D.), and through the University of Cyprus Articles 3/311 and 3/346 (C.D.).
PY - 2013/12
Y1 - 2013/12
N2 - The familial hematuric diseases are a genetically heterogeneous group of monogenic conditions, caused by mutations in one of several genes. The major genes involved are the following: (i) the collagen IV genes COL4A3/A4/A5 that are expressed in the glomerular basement membranes (GBM) and are responsible for the most frequent forms of microscopic hematuria, namely Alport syndrome (X-linked or autosomal recessive) and thin basement membrane nephropathy (TBMN). (ii) The FN1 gene, expressed in the glomerulus and responsible for a rare form of glomerulopathy with fibronectin deposits (GFND). (iii) CFHR5 gene, a recently recognized regulator of the complement alternative pathway and mutated in a recently revisited form of inherited C3 glomerulonephritis (C3GN), characterized by isolated C3 deposits in the absence of immune complexes. A hallmark feature of all conditions is the age-dependent penetrance and a broad phenotypic heterogeneity in the sense that subsets of patients progress to added proteinuria or proteinuria and chronic renal failure that may or may not lead to end-stage kidney disease (ESKD) anywhere between the second and seventh decade of life. In addition to other excellent laboratory tools that assist the clinician in reaching the correct diagnosis, the molecular analysis emerges as the gold standard in establishing the diagnosis in many cases of doubt due to equivocal findings that complicate the differential diagnosis. Recent work led to the description of candidate genetic modifiers which confer a variable risk for progressing to chronic renal failure when co-inherited on the background of a primary glomerulopathy. Finally, more families are still waiting to be studied and more genes to be mapped and cloned that are responsible for other forms of heritable hematuric diseases. The study of such genes and their protein products will likely shed more light on the structure and function of the glomerular filtration barrier and other important glomerular components.
AB - The familial hematuric diseases are a genetically heterogeneous group of monogenic conditions, caused by mutations in one of several genes. The major genes involved are the following: (i) the collagen IV genes COL4A3/A4/A5 that are expressed in the glomerular basement membranes (GBM) and are responsible for the most frequent forms of microscopic hematuria, namely Alport syndrome (X-linked or autosomal recessive) and thin basement membrane nephropathy (TBMN). (ii) The FN1 gene, expressed in the glomerulus and responsible for a rare form of glomerulopathy with fibronectin deposits (GFND). (iii) CFHR5 gene, a recently recognized regulator of the complement alternative pathway and mutated in a recently revisited form of inherited C3 glomerulonephritis (C3GN), characterized by isolated C3 deposits in the absence of immune complexes. A hallmark feature of all conditions is the age-dependent penetrance and a broad phenotypic heterogeneity in the sense that subsets of patients progress to added proteinuria or proteinuria and chronic renal failure that may or may not lead to end-stage kidney disease (ESKD) anywhere between the second and seventh decade of life. In addition to other excellent laboratory tools that assist the clinician in reaching the correct diagnosis, the molecular analysis emerges as the gold standard in establishing the diagnosis in many cases of doubt due to equivocal findings that complicate the differential diagnosis. Recent work led to the description of candidate genetic modifiers which confer a variable risk for progressing to chronic renal failure when co-inherited on the background of a primary glomerulopathy. Finally, more families are still waiting to be studied and more genes to be mapped and cloned that are responsible for other forms of heritable hematuric diseases. The study of such genes and their protein products will likely shed more light on the structure and function of the glomerular filtration barrier and other important glomerular components.
KW - Alport-TBMN-CFHR5/C3GN-GFND
KW - COL4-CFHR5-FN1
KW - Familial microscopic hematuria
KW - Genetic and phenotypic heterogeneity
KW - Genetic modifiers
UR - http://www.scopus.com/inward/record.url?scp=84890039318&partnerID=8YFLogxK
U2 - 10.1093/ndt/gft253
DO - 10.1093/ndt/gft253
M3 - Review article
C2 - 24046192
AN - SCOPUS:84890039318
SN - 0931-0509
VL - 28
SP - 2946
EP - 2960
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 12
ER -