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      Organ-Specific Collagen Expression: Implications for Renal Disease

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          Chronic kidney disease is characterized by progressive accumulation of extracellular matrix and scarring, leading to the loss of kidney function. Excess deposition of the collagen family of proteins is the hallmark of kidney fibrosis. In this review, we survey the collagens that are associated with renal disease and we highlight the use of a transgenic approach to identify cis-acting sequences in the collagen type I promoter which are capable of directing collagen type I expression specifically in the kidney. Ultimately it may be possible to use this approach to halt the accumulation of collagen selectively in this organ.

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          Most cited references 24

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          Collagens and collagen-related diseases.

          The collagen superfamily of proteins plays a dominant role in maintaining the integrity of various tissues and also has a number of other important functions. The superfamily now includes more than 20 collagen types with altogether at least 38 distinct polypeptide chains, and more than 15 additional proteins that have collagen-like domains. Most collagens form polymeric assemblies, such as fibrils, networks and filaments, and the superfamily can be divided into several families based on these assemblies and other features. All collagens also contain noncollagenous domains, and many of these have important functions that are distinct from those of the collagen domains. Major interest has been focused on endostatin, a fragment released from type XVIII collagen, which potently inhibits angiogenesis and tumour growth. Collagen synthesis requires eight specific post-translational enzymes, some of which are attractive targets for the development of drugs to inhibit collagen accumulation in fibrotic diseases. The critical roles of collagens have been clearly illustrated by the wide spectrum of diseases caused by the more than 1,000 mutations that have thus far been identified in 22 genes for 12 out of the more than 20 collagen types. These diseases include osteogenesis imperfecta, many chondrodysplasias, several subtypes of the Ehlers-Danlos syndrome, Alport syndrome, Bethlem myopathy, certain subtypes of epidermolysis bullosa, Knobloch syndrome and also some cases of osteoporosis, arterial aneurysms, osteoarthrosis, and intervertebral disc disease. The characterization of mutations in additional collagen genes will probably add further diseases to this list. Mice with genetically engineered collagen mutations have proved valuable for defining the functions of various collagens and for studying many aspects of the related diseases.
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            Renal basement membrane components.

            Renal basement membrane components. Basement membranes are specialized extracellular matrices found throughout the body. They surround all epithelia, endothelia, peripheral nerves, muscle cells, and fat cells. They play particularly important roles in the kidney, as demonstrated by the fact that defects in renal basement membranes are associated with kidney malfunction. The major components of all basement membranes are laminin, collagen IV, entactin/nidogen, and sulfated proteoglycans. Each of these describes a family of related proteins that assemble with each other in the extracellular space to form the basement membrane. Over the last few years, new basement membrane components that are expressed in the kidney have been discovered. Here, the major components and their localization in mature and developing renal basement membranes are described. In addition, the phenotypes of basement membrane component gene mutations, both naturally occurring and experimental, are discussed, as is the aberrant deposition of basement membrane proteins in the extracellular matrix in several renal diseases.
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              COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome.

              COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome. Mutations of the type IV collagen COL4A5 gene cause X-linked Alport syndrome (ATS). Mutations of COL4A3 and COL4A4 have been reported both in autosomal-recessive and autosomal-dominant ATS, as well as in benign familial hematuria (BFH). In the latter conditions, however, clinical features are less defined, few mutations have been reported, and other genes and non-genetic factors may be involved. We analyzed 36 ATS patients for COL4A3 and COL4A4 mutations by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Sporadic patients who had tested negative for COL4A5 mutations were included with typical cases of autosomal recessive ATS to secure a better definition of the phenotype spectrum. We identified seven previously undescribed COL4A3 mutations: in two genetic compounds and three heterozygotes, and one in COL4A4. In agreement with the literature, some of the mutations of compound heterozygotes were associated with microhematuria in healthy heterozygous relatives. The mutations of heterozygous patients are likely dominant, since no change was identified in the second allele even by sequencing, and they are predicted to result in shortened or abnormal chains with a possible dominant-negative effect. In addition, both genes showed rare variants of unclear pathogenicity, and common polymorphisms that are shared in part with other populations. This study extends the mutation spectrum of COL4A3 and COL4A4 genes, and suggests a possible relationship between production of abnormal COL IV chains and dominant expression of a continuous spectrum of phenotypes, from ATS to BFH.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                February 2006
                15 November 2005
                : 102
                : 3-4
                : e71-e75
                Renal Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, UK
                89684 Nephron Exp Nephrol 2006;102:e71–e75
                © 2006 S. Karger AG, Basel

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                Figures: 1, Tables: 1, References: 35, Pages: 1
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