Defects in type IV collagen, a collagenous protein involved in the formation of basement membranes, have been implicated in hereditary Alport's syndrome and acquired Goodpasture's syndrome. Mutations in genes corresponding to the building blocks of type IV collagen cause Alport's syndrome, whereas autoantibodies against structures that are usually hidden in the recesses of collagen IV cause Goodpasture's syndrome.

Alport's Syndrome, Goodpasture's Syndrome, and Type IV Collagen

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.

https://www.tandfonline.com/doi/pdf/10.3109/07853890109002055

Collagens and collagen-related diseases

https://www.kidney-international.org/article/S0085-2538(15)52297-7/pdf

The spectrum of podocytopathies : A unifying view of glomerular diseases

Four decades have passed since the first discovery of collagen IV by Kefalides in 1966. Since then collagen IV has been investigated extensively by a large number of research laboratories around the world. Advances in molecular genetics have resulted in identification of six evolutionary related mammalian genes encoding six different polypeptide chains of collagen IV. The genes are differentially expressed during the embryonic development, providing different tissues with specific collagen IV networks each having unique biochemical properties. Newly translated α-chains interact and assemble in the endoplasmic reticulum in a chain-specific fashion and form unique heterotrimers. Unlike most collagens, type IV collagen is an exclusive member of the basement membranes and through a complex inter- and intramolecular interactions form supramolecular networks that influence cell adhesion, migration, and differentiation. Collagen IV is directly involved in a number of genetic and acquired disease such as Alport's and Goodpasture's syndromes. Recent discoveries have also highlighted a new and direct role for collagen IV in the development of rare genetic diseases such as cerebral hemorrhage and porencephaly in infants and hemorrhagic stroke in adults. Years of intensive investigations have resulted in a vast body of information about the structure, function, and biology of collagen IV. In this review article, we will summarize essential findings on the structural and functional relationships of different collagen IV chains and their roles in health and disease.

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Mammalian collagen IV.

Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect.

http://www.alport.de/homepage/JASNGross2003.pdf

X-Linked Alport Syndrome: Natural History and Genotype-Phenotype Correlations in Girls and Women Belonging to 195 Families: A "European Community Alport Syndrome Concerted Action" study

Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, non-sense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.

http://alport.de/homepage/JASNGross2000.pdf

Sarka Krejcova

Papers

X-linked Alport Syndrome Natural History in 195 Families and Genotype- Phenotype Correlations in Males