Identification of the genes responsible for Alport syndrome and polycystic kidney diseases

Abstract

Alport syndrome (AS) is a hereditary disease of basement membranes characterized by progressive renal failure and deafness. The type IV collagen matrix is the major structural component of the glomerular basement membrane (GBM). We have identified mutations in the α3(IV) and α4(IV) collagen genes in autosomal recessive AS. This finding suggests that both genes are responsible for autosomal recessive AS. Autosomal dominant polycystic kidney disease (ADPKD) consists of at least three genetically distinct disorders characterized by cyst formation and enlargement of the kidneys. A second gene for ADPKD was identified by positional cloning. Nonsense mutations in this gene segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino-acid similarity with PKD1, with the C. elegans homolog of PKD1, and with the family of voltage-activated calcium channels, and it contains a potential calcium-binding protein. An inversion of embryonic turning (inv) mutation was generated in a mouse by random insertional mutagenesis. The phenotype of the inv mouse was a consistent mirror-image reversal of left-right asymmetry (situs inversus) accompanied by the formation of cysts in the kidney. We have identified a responsible gene for the inv mutation by positional cloning. The cDNA of the candidate gene has a long open reading frame that encodes 1062 amino acids. It does not contain a signal peptide or transmembrane domain, indicating that it is probably an intracellular protein. The most distinctive feature of this candidate protein is the presence of 15 successive repeats of an Ank/Swi6 motif, consisting of about 33 amino acids.