Autosomal recessive Alport syndrome: mutation in the COL4A3 gene in a woman with Alport syndrome and posttransplant antiglomerular basement membrane nephritis.

Autosomal recessive Alport syndrome can arise from a mutation in either of the genes COL4A3 and COL4A4 on chromosome 2, which encode, respectively, the alpha 3 and alpha 4 chains of Type IV collagen. This report describes a mutation in COL4A3 in a girl who presented at age 5 with hematuria and proteinuria, lacking any family history of renal disease. Renal biopsy at age 8 showed immunoglobulin A nephropathy and Alport syndrome. Sensorineural deafness developed during adolescence, and the patient's renal disease progressed to terminal renal failure by age 20. She received a living related donor renal allograft at age 20 and developed antiglomerular basement membrane nephritis of the allograft 8 months after transplantation. Amplification and sequencing of exon 5 of COL4A3 (counting from the 3' end of the gene) revealed a 7-base-pair deletion, producing a shift of the reading frame and the creation of a premature stop codon. Each parent was heterozygous for the normal and mutant exon 5 sequences. This mutation in COL4A3 would result in the loss of 222 amino acids from the carboxy-terminal noncollagenous domain of the alpha 3(IV) chain. The mutant chain would be unable to form trimers with other Type IV collagen alpha chains. In addition, the mutant chain would lack the Goodpasture epitope, which resides in the carboxy-terminal noncollagenous domain of the alpha 3(IV) chain. The absence of this epitope may underly the subsequent development of anti-glomerular basement membrane nephritis in the allograft.