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From Dr. Catherine Marley:
March 2007

Good news from Dr. Whiteley! She has results coming out now on the test for the “C” mutation. The previously seen sequence mutations “A” and “B” that affected the same gene seem now to have represented alteration in the nucleotides of the gene, peculiar to Lhasas and Shih-Tzus, that may only represent a “weak spot” in the DNA which is susceptible to mutation. The real culprit seems to be “C”, also a mutated sequence in the same gene.

Mary has found a 100% correspondence between the disease and the presence of “C”.  She has also found that “C” prevents the formation of any protein by the gene.  All active genes are templates for proteins.  These proteins are the enzymes and messengers that control development and all chemical functions of the body.  Whatever the critical protein is, that controls some aspect of development of the renal system, IT IS NOT MADE by the chromosome with the “C” mutation.  The implication of this is that if there are two “C” mutations the protein is completely missing.  And if the animal has only one “C”, the animal may have some deficiency or delay in the manufacture of the essential protein which governs development of the kidney.  The former would totally prevent differentiation of the renal system, while the latter would present itself as a variable degree of incomplete development of the kidney – which is exactly what we see in HKD/JRD.

The further implications of this fit very well with what Mary has discovered. NONE of her DNA specimens so far, taken from living animals, have contained two copies of the “C” mutation. Since the heterozygous state (one mutation, one normal) is fairly common, it is statistically possible to have NO homozygotes ONLY if all the homozygotes fail to develop in utero. If the protein in question is one that induces the embryonic mesenchyme to develop a kidney, and possibly other mesenchymal structures, then the embryo which lacks that very early induction protein most likely will not develop past an early stage.

Normally,  breeding of two carriers (heterozygotes) produces 25% clears, 50 % heterozygotes, and 25% homozygotes. Our previous understanding of the breeding statistics was that 75% of the offspring of two carriers were at risk of having and transmitting HKD/JRD.  The “C” mutation improves the odds that an individual in one of our litters is a “clear” since  homozygotes are all lost at conception or shortly thereafter.  What we will actually see in our litters from two heterozygous animals, is 33% clears, and 67% heterozygotes.   Of course, because some embryos are lost, litters might be smaller. 

Mary should have some results soon for all you Apso owners and breeders who sent in specimens.  Some of the results may be disappointing to those who originally had the good news that their animals were free of the “A” and “B” mutations,  But the advice remains the same because the facts are still the same.  Very few of the animals with the “C” mutation are clinically affected by HKD/JRD, though they are able to transmit the disease to offspring.  Our breeding programs will need to continue to use the heterozygotes so as not to cause another “genetic bottleneck”  like the original founder effect.  If we do this, we can, through testing, gradually eliminate the gene, while preserving the diversity of the breed. 

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