MAJOR COL4A5 GENE REARRANGEMENTS IN PATIENTS WITH JUVENILE TYPE ALPORT SYNDROME

Mutations in the COL4A5 gene, which encodes the a5 chain of type IV co llagen, are found in a large fraction of patients with X-linked Alport syndrome. The recently discovered COL4A6, tightly linked and highly h omologous to COL4A5, represents a second candidate gene for Alport syn drome. We analyzed 177 Italian Alport syndrome families by Southern bl otting using cDNA probes from both COL4A5 and COL4A6. Nine unrelated f amilies, accounting for 5% of the cases, were found to have a rearrang ement in COL4A5. No rearrangements were found in COL4A6, with the exce ption of a deletion encompassing the 5' ends of both COL4A5 and COL4A6 genes in a patient with Alport syndrome and leiomyomatosis. COL4A5 re arrangements were all intragenic and included 1 duplication and 7 dele tions. Polymerase chain reaction (PCR) analysis was carried out to cha racterize deletion and duplication boundaries and to predict the resul ting protein abnormality. The two smallest deletions involved a single exon (exons 17 and 40, respectively), while the largest ones spanned exons 1 to 36. The clinical phenotype of patients in whom a rearrangem ent in COL4A5 was detected was severe, with progression to end-stage r enal failure in juvenile age and hypoacusis occurring in most-cases. T hese data have some important implications in the diagnosis of patient s with Alport syndrome. (C) 1995 Wiley-Liss, Inc.