Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)

Legacy Department



Clark, Leigh Anne

Committee Member

Morris , James C.

Committee Member

Morris , Meredith T.

Committee Member

Murphy , Keith E.

Committee Member

Starr-Moss , Alison N.


The glomerular basement membrane (GBM) of the kidney is highly specialized and required for filtration of waste products from the bloodstream. One of the major structural and functional units of the GBM is a network composed of type IV collagen heterotrimers, or protomers. Early in development of the human and dog, an isoform switch occurs, and the α1α1α2 (IV) network found in the nascent GBM is replaced with α3α4α5 (IV) protomers. Mutations in any of the genes encoding proteins found in the mature GBM network may prevent protomer formation and cause a progressive disorder leading to end stage renal failure (ESRD). In the human, the disease is known as Alport syndrome (AS) and is characterized by proteinuria, hematuria, and in half of affected patients, deficits in hearing. The GBM undergoes characteristic ultrastructural changes, and immunostaining of renal samples reveals a loss of α3 (IV) and α5 (IV) proteins with a corresponding increase in α1 (IV) chains. Hereditary nephropathy (HN) is the canine counterpart of AS and has been reported in different breeds. Affected dogs display clinicopathological signs identical to those described in AS patients, with the exception of hearing loss. There were two major objectives for this project. The first objective was to amplify and sequence a region previously lacking coverage on CFA25 between the genes encoding the α3 (IV) and α4 (IV) chains. This was necessary in order to span gap regions in the canine reference genome. The second objective was to identify the mutation causative for HN in a breed not previously reported to present with the disease.