COL4A5 deletions in three patients with Alport syndrome and posttransplant antiglomerular basement membrane nephritis.

Mutations in the COL4A5 gene encoding the alpha 5 chain of Type IV collagen were identified in three men with Alport syndrome and posttransplant antiglomerular basement membrane (GBM) nephritis by the use of Southern analysis, polymerase chain reaction amplification of genomic DNA, and reverse transcription and amplification of lymphocyte RNA. Two related patients (M.C. and J.M.) exhibited deletion of COL4A5 beginning in the 5'-most portion of the gene and extending through the 3' untranslated region, whereas the third patient (J.E.) had an intragenic deletion encompassing Exons 4 through 47. Combined with previously reported data, these findings suggest that the incidence of deletions of COL4A5, as opposed to other COL4A5 mutations, is much higher in Alport patients who develop posttransplant anti-GBM nephritis than in the general Alport population. Immunofluorescence studies of kidney from Patient J.E. showed no reactivity of GBM with monoclonal antibodies directed against the alpha 3, alpha 4, and alpha 5 chains of Type IV collagen. This finding confirms that the mutation affecting the alpha 5(IV) chain can interfere with the incorporation of alpha 3(IV) and alpha 4(IV) into the GBM.