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Juvenile renal dysplasia (JRD), also referred to
as juvenile nephropathy, is an important category of kidney diseases in canines.
Dysplasia is defined as abnormal growth or development of cells or organs. In
the case of JRD the kidney fails to develop properly during embryogenesis in the
womb. At birth immature structures consisting of undifferentiated fetal cells or
tissue types are found in the kidney, and are persistent throughout the life of
the animal.
Many breeds of dogs are afflicted with JRD, and this has been documented in both
veterinary text books, as well as case reports and articles in the scientific
literature(see:
breeds with rd). Of note is that JRD in these breeds share a common
phenotype, characterized by immature glomeruli, and/or tubules and persistent
mesenchyme. Given the evolution of the domestic dog it would not be surprising
if the disease causing mutation for JRD is conserved among the various breed. In
fact this has been shown to be true for type I von Willebrands disease, and
epilepsy . The recently discovered mutation for a form of epilepsy in dogs
has also been found in wolves.
The morphological features of JRD in dogs differ slightly from those in
man, and therefore selection of genes that are responsible for this disease
is somewhat difficult.
During the development of the fetus, certain genes act in a pathway or cascade
to direct the development of the various organs and structures that make up the
body (think of it as dominos:if one domino is missing the other ones wont
perform their task in the array). Since every cell contains two copies of every
gene, one non-mutated copy may be sufficient to complete to cascade (recessive
inheritance). The human genome contains about 20,000 to 25,000 genes, and the
canine genome is likely to contain about the same number. Of these several
hundred or more may be dedicated to the maturation of specific organs. Not all
of these “tissue specific” genes are absolutely essential to the development of
specific cell types, as has been shown in “knockout mice”, where genes have been
completely eliminated with no observable effect on the animal. In the case of
renal dysplasia in model organisms such as the mouse, mutated transcription
factors (genes that code for proteins that turn on other genes) or growth
factors (genes that code for proteins that promote the growth of cells), have
been implicated in causing the disease(Ref).
The mode of inheritance of JRD has been widely debated, as this disease can
present itself with a wide range of symptoms and pathological findings.
Definitive diagnosis of JRD is done by a wedge biopsy which reveals dysplastic
lesions, including abnormal ducts, and glomeruli. Individuals with an abnormal
biopsy can be asymptomatic, showing no signs of the disease, On the other hand,
they may present with classic signs of chronic end stage renal failure (4), or
somewhere between these two extremes. Given this broad spectrum of symptoms
affected individuals often go unnoticed, and remain in the breeding population.
This is why development of a genetic test is critical to the management and
elimination of this disease. Further a genetic test will shed light on the mode
inheritance.
The purpose of this research is to examine possible candidate genes in the above
categories that are known to be expressed in a spatial and temporal manner in
the developing kidney within the structures that are ultimately affected in
animals with JRD. The ultimate goal is to find a disease causing mutation, and
develop a genetic test for management and elimination of this disease (see :
kinds of genetic
tests). Only a direct test is acceptable for proper management of this
disease. |