Molecular genetics of Alport syndrome

Abstract

Alport syndrome is a progressive hereditary kidney disease characterized by hematuria, sensorineural hearing loss and ocular lesions with structural defects in the glomerular basement membrane (GBM). The gene frequency has been estimated to be 1:5000. The disease is primarily X chromosome-linked, but autosomal forms have also been reported. The X-linked form has been shown to be caused by mutations in a recently identified alpha 5(IV) collagen chain gene (COL4A5). We have isolated cDNA clones for providing the entire primary structure of the human alpha 5(IV) chain. The gene has been located to the Xq22 region. Using antibodies against synthetic peptides, the alpha 5(IV) chain was shown to be located in the kidney only in the glomerular basement membrane. Thus far, the exon-intron structure has been determined for a large portion of the gene which probably has a size of over 200 kb. Numerous different mutations have been identified in the COL4A5 gene. The mutations include single base mutations, large deletions and other major rearrangements such as inversion and duplication. The consequences of the mutations observed can be considered sufficient to cause structural and functional defects in the type IV collagen molecule and, therefore, also the GBM network. This, in turn can explain the disruption of the GBM and hematuria occurring in these Alport patients. Alport syndrome is the first genetic basement membrane and kidney disease whose gene has been cloned. These recent results have enabled the development of antibodies and DNA probes for accurate diagnosis of Alport syndrome.

Systemic administration of naked DNA with targeting specificity to mammalian kidneys

“…This disease, with a gene frequency of 1:5000, 33 is mainly X-chromosomelinked and caused by mutations in the type IV collagen a5 chain (COL4A5). [34][35][36] The symptoms of Alport's syndrome are mild to moderate hematuria and proteinuria, and the disease usually progresses to end-stage renal failure in males, leading to a need for continuous dialysis or renal transplantation. By delivering a normal copy of the type IV collagen a5 chain gene into cells of patients with X-linked Alport's syndrome, the defect could theoretically be corrected and the renal failure prevented.…”

Comparative distribution of the alpha 1(IV), alpha 5(IV), and alpha 6(IV) collagen chains in normal human adult and fetal tissues and in kidneys from X-linked Alport syndrome patients.

“…More recently, we and others have isolated a6 (IV), a new type IV collagen chain that had not been detected biochemically (14)(15)(16). The complete primary structures of all six a chains are known: each a chain possesses a -1,400-residue collagenous domain that is interrupted by [21][22][23][24][25][26] noncollagenous sequences and a globular, -230-residue COOH-terminal noncollagenous (NC1) domain. By comparing the primary structures of these chains, we divided type IV collagens into two structural families: the al-like family, containing the al (IV), a3 (IV), and a5 (IV) chains and the a2-like family, consisting of the a2 (IV), a4 (IV), and a6 (IV) chains (14,15).…”

Laminin and collagen IV subunit distribution in normal and neoplastic tissues of colorectum and breast

“…Novel collagen IV subunits have been found more recently, and these include the oc3(IV), cx4(IV) and cx5(IV) subunits (Tryggvason et al, 1993). The laminin molecule is also a heterotrimer of different subunits .…”