By PamThe recent news from the USA (see below) that research workers at Ohio State University Veterinary School have identified a genetic defect thought to be responsible for Hypertrophic Cardiomyopathy in Maine Coon cats is of great interest to cat breeders worldwide.
Hypertrophic Cardio-myopathy (HCM) is one cause of myocardial hypertrophy (ie thickening of the muscle of the heart wall) which is the most common form of heart disease in cats.
HCM is the term used for primary disease of the heart muscle which has been shown to have a genetic basis in man and other animals. Earlier studies in a colony of Maine Coon cats in the USA have strongly indicated an autosomal dominant pattern of inheritance although the specific genetic mutation has not hitherto been identified. Although the disease has been most extensively studied in one line of Maine Coons it is very important to understand that the disease is not specific to or even particularly common in this breed and all domestic cat breeds including non-pedigree cats are probably susceptible.
HCM is a very serious disease as it alters the structure of the heart leading to mechanical dysfunction which causes severe clinical problems such as congestive heart failure, thrombo-embolism and even sudden death. It can affect cats of any age but usually affects young adults under five years old. Males tend to be affected at a younger age than females.
The main problem with HCM from a breeders point of view and the reason why the identification of a specific genetic defect for which a DNA test can be developed would be so useful is that the disease may not develop until quite late in a cats life (after it has produced or sired kittens) and is difficult to diagnose and differentiate from other non-genetic forms of myocardial hypertrophy even with sophisticated techniques such as Doppler Echocardiography.
Myocardial hypertrophy can occur as a secondary response to any condition which causes the heart muscle to work persistently harder to meet the oxygen demands of the body. In young cats it is often associated with other anatomical heart defects. In older cats chronic kidney disease and hyperthyroidism which cause hypertension (ie persistently raised blood pressure) are the two most common conditions to which it is linked.
A DNA test which could identify kittens affected with Primary (Genetic) HCM early in life, before breeding would be of great value in helping breeders select against this disease in their cats. However it is important not to be overly optimistic about this possibility.
The situation is unlikely to be as simple as that which exists with Polycystic Kidney Disease(PKD. In PKD the majority of cases in Persians and Exotic Shorthairs have been found to be associated with one particular autosomal dominant gene for which a DNA test is now routinely available. In man many different genetic forms of HCM are recognised and it is likely that a similar situation exists in cats so one simple DNA test is very unlikely to identify all forms of the disease.
However it is an interesting development and we must hope that a test for at least one type will become available in the not too distant future.
Dr Kittleson and Dr Kate Meurs, DVM, Diplomate ACVIM (Cardiology),Ohio State University, and their respective staffs, have identified a mutation in DNA that appears to cause HCM in Maine Coon cats in the Davis colony. The paper (The abstract of which is reproduced below for the geneticists among our readers!) has been submitted for publication, and the abstract was presented in June, at the ACVIM forum.
This is a point mutation in Myosin Binding Protein C, and is in an exon that has not been documented to cause HCM in humans, although there are certainly human HCM mutations in this gene (just not in the area of the gene where the Maine Coon mutation was seen).
The mutation changes the amino acid alanine into proline. When this change is run through a computer simulation, the Myosin Binding Protein C molecule is definitely malformed - it is folded on abnormal manner, and it is postulated that this protein would not be able to mechanically fulfil its function in the sarcomere. This mutation also explains the reduction in myomesin documented by these same researchers several years ago.
Dr Meurs has done DNA sequencing work on this gene, and has developed an RFLP DNA test, and the results from these two methods are in agreement. Work will continue to determine if this is the only mutation seen in Maine Coons. The issues surrounding the standardization of this test, the method for disseminating sample kits and collecting samples, cost, etc, are a bit unclear at present. This information will be made public in the coming days and weeks. Suffice to say that a test is coming, really coming, and soon.
This is the very first important step towards developing a gene-marker test. In the USA the licence holder for the PKD-test, Van Haeringen laboratories, has in the mean time collected blood samples of HCM-positive cats of other breeds as well (like British SH, Cornish Rex, Ragdoll, NFO and others). It is hoped they can be sent off to Leslie Lyons soon so it can be found out if in these breeds the gene location is the same.
ABSTRACT Number 58
IDENTIFICATION OF A MISSENSE MUTATION IN THE CARDIAC MYOSIN BINDING PROTEIN C GENE IN A FAMILY OF MAINE COON CATS WITH HYPERTROPHIC CARDIOMYOPATHY.
By: Meurs K, Sanchez X, David R, Bowles NE, Towbin JA, Reisser PJ, Kittleson JA, Munro, MJ, Dryburgh K, Boyer M, Marthur D, MacDonald KA, Kittleson MD. The Ohio State University, Columbus, Ohio, Baylor College of Medicine, Houston TX, University of California, Davis CA.
A feline model of familial hypertrophic cardiomyopathy (HCM) has been previously identified in Maine Coon cats. The disease is inherited as an autosomal dominant trait, develops during early to mid-adult life, and often causes heart failure, systemic thromboembolism and sudden death. We hypothesed that a sarcomeric gene mutation is present in this animal model.
The objectives were to determine if a sacromeric mutation is present and to determine its effect on the protein. Disease status of Maine Coon cats was verified through repeated echocardiac examinations (affected = 16; unaffected = 7). DNA was extracted from white cells from the 23 Maine Coon and 106 control cats. Myocardium was collected from Maine Coon cats that died (n=8) and from control cats (n=3). Primers were developed from amplifications of exonic regions of several feline sarcomeric genes. including the cardiac myosin binding protein C (cMyBP-C) gene, using known human sequences and Primer3 software. Primers were optimized and DNA was amplified, purified and sequenced.
Sequences were compared for base pair changes. Base pair alterations were avaluated to determine if they changed a conserved amino acid and the computed structure of the protein. Western blot analysis using a cMyBP-C antibody was performed on frozen myocardial tissue from affected and unaffected cats.
A single base pair change (G to C) was identified within exon 3 in all of the Maine Coon cats with HCM but none of the unaffected Maine Coon cats or control cats. The missense mutation changed a conserved amino acid from alanine to proline and resulted in a computed alteration in the conformation of the molecule Immunobinding demonstrated a significant reduction in cMyBP-C in the myocardium from affected cats when compared to unaffected cats.
Conclusions: We conclude that we have identified a spontaneous sarcomeric mutation associated with HCM in the cat.
It is a missense mutation in the feline cMyBP-C gene and the mutation changes a conserved amino acid resulting in alteration of and a reduction in cMyBP-C protein.
