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Identification of genetic markers for an inherited craniofacial deformity syndrome in Burmese cats.

(project continuation from initiation in 1994)

Leslie A. Lyons, Ph.D., Marilyn Menotti-Raymond, Ph.D., and Stephen J. O'Brien, Ph.D.

Laboratory of Genomic Diversity, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, MD 21702-1201

09 December 1996

Hilary Helmrich
President
Robert Winn Foundation
1805 Atlantic Avenue
PO Box 1005
Manasquan, NJ 08736-0805

Dear Hilary,

Enclosed is a proposal for the continuation of the Burmese head deformity project. The abstract is suitable for any usage. Several samples still need to be collected, but we have an adequate number of deformities to proceed with searching for a marker. The success of the project depends on the microsatellite markers now, not the acquisition of samples. Whether a microsatellite will be a useful marker will be luck of the draw. I do not anticipate requesting future funds for the project since the limitation is our resources, not those provided by the cat fancy. If we are lucky enough to find a marker, future studies could focus on a specific gene investigation, but that is beyond the request of the breeders. Please contact me with any questions on the project. I do not anticipate being away from the lab for an extended period.

Best regards,

Leslie A. Lyons, Ph.D.

Senior Staff Fellow

Abstract

The Laboratory of Genomic Diversity at the National Cancer Institute is continuing its investigation of the Burmese head defect. Over 250 samples from Burmese, Foreign Burmese, Egyptian Mau, American Shorthairs, Scottish Folds, and random bred cats have been collected for the study. Thirty deformed kittens have been acquired, including deformed kittens from Belgium. The gene causing the deformity has spend to other breeds and into Europe. The microsatellites developed in the lab for marker testing have proven to be useful and a full genome search of over 300 microsatellites will be used to find a marker for the deformity. The deformity has been confirmed to act in an autosomal recessive inheritance pattern and no cats with the "more extreme" head type have proven clear of carrying the deformity. The possibility of a clear "more extreme" cat remains and should not be abandoned, but using "more extreme" cats in other breeding programs is not recommended and should be confined to "more extreme" Burmese breeding programs. Samples from Tonkinese, Bombays, and the siblings and parents of deformed kittens need to be acquired. Specific breeders will be contacted to participate. These breeders will have cats which are major contributors to the breeds gene pools We will attempted to complete the collection of 25 cats for each participating breed, Burmese, Tonkinese, ASH, E.Mau, Scottish Fold, and Bombay by requesting samples from the top winners and cats who have received distinguished merit honors. A standard set of thirty microsatellites will be genotyped in these cats to determine the relative fitness of the Burmese breed in the cat fancy. Detection of a marker for the deformity will be performed by standard linkage analyses and homozygosity mapping.

Background

The Burmese head deformity project was initiated by the Laboratory of Genomic Diversity (LGD) in response to a request by the National Alliance of Burmese Breeders (NABB) to the Winn Foundation. The Winn Foundation responded with a request for proposals specific to this project. The LGD's project was divided into three parts that would address five questions; 1) determine the mode of inheritance of the Burmese craniofacial deformity, 2) determine the mode of inheritance of the dichotomized facial structure for the Burmese, 3) determine if the deformity can be separated from the "more extreme" Burmese phenotype, 4) develop genetic markers for the possible identification of deformity carriers, and 5) provide suggestions for the eradication of the deformity. It was anticipated that the collection of the data and the analyses of the modes of inheritance, and baseline breed should be completed in 12-18 months, but identification of markers for the deformity or head structure would be unpredictable and would become a long-term project for the laboratory. The three parts to the project included, 1) pedigree ascertainment, 2) breed sample collection, and, 3) genetic marker characterization and isolation

Progress

The mode of inheritance for the Burmese head deformity has been comfirmed to be autosomal recessive. The previous studies and literature had suggested this mode of inheritance, but confusing in nomenclature has occurred, giving the impression that a different pattern has been suggested. The deformed kittens only occur when two copies of the defective gene have been inherited, one from each parent. Several catteries have provided their breeding records which confirm the autosomal recessive inheritance pattern. The most compelling data was obtained from France and Belgium. With the importation of one "more extreme" Burmese, deformed kittens were produced when the imported cat was found in both the maternal and paternal lineage. Data from outcrosses to American Shorthairs, Scottish Folds, and Bombays have supported this evidence. A detailed formal analysis using segregation programs was not necessary for this aspect of the project. The mode of inheritance of the head structure, "more extreme" or "less extreme", has not been formally addressed. The development of measurements of the skull and facial structure has been difficult to obtain. The coordination of specific individuals to evaluate head types and to get all the cats available at specific ages has also been difficult. The correlation with the "more extreme" head type and cats that have kittens with the deformity is extremely strong. We have obtained no evidence that a "more extreme" cat has proven to be clear of producing the deformity. At this time, no conclusions can be made as to whether the gene(s) involved with the head structure is/are the exact same gene(s) producing the deformity. Normally, many genes are involved with determining the structure of the head. The deformity is caused by a single gene, acting autosomal recessively. We suggest that the gene for the deformity is physically near the genes involved with the "more extreme" head type, if not one of the genes involved with the structure of the head. If so, the use of genetic markers could identify cats that have most of the genes causing the "more extreme" head type, but have lost the gene causing the deformity. This can occur by the natural process of recombination. The frequency of the occurrence is determined by the distance between the genes involved. Since many cats have not been found to be clear of the defect but of the "more extreme" head type, the physical location of the genes involved must be extremely close. Thus, we can not determine if the deformity can be separated from the "more extreme" Burmese head type until a cat is test mated to be proven clear of carrying the deformity, or until genetic markers are found for the deformity. Over 250 samples have been collected for the study and are detailed in Table 1. Thirty deformed kittens have been collected from ten different litters, including deformities collected in Belgium. The prelimary baseline data requires 25-30 samples from cats who represent the gene pool of each breed involved in the study. The collection of samples from breeds other than Burmese and Foreign Burmese has been hampered by the impression of finding Burmese genes in cats which are not Burmese. The investigators have worked hard to dispell this misconception and emphasize that the data is confidential. Breeders who have participated from the other breeds have had a general interest in genetics and the health of cats in the cat fancy. Many of the samples from the other breeds are from only a few catteries, we must be sure to not use closely related cats in the analysis, and attempt to obtain cats which represent the gene pools of each breed. A general request for samples has been published and we intend to focus heavily on Tonkinese and Bombay breeders. The lab has obtained veterinary support and now can manage field trips to catteries more readily. Preliminary data has shown that the microsatellites will be powerful markers for the study and are capable of identifying a marker for the deformity. Most of the microsatellites tested in the Burmese have been heterozygous and should be informative for the study. No candidates genes for the deformity have been identified in the literature or from discussions with cranial-facial specialists at Johns Hopkins University, thus a genome wide search with all the available 300 microsatellites will be initiated to find a marker for the deformity. The samples acquired from the outcrosses to other breeds and samples collected from Europe will be particularly valauble in the search for a marker. The Burmese deformity has spread to other fancy cat breeds and to the Burmese in Europe. No evidence has been obtained for the deformity occurring in England or Australia. We recommend that "more extreme" cats are not used in other breeding programs or used as exports. The use of "more extreme" Burmese should be confined to "more extreme" Burmese breeding programs only.

Future Goals

The collection of 25-30 cats from each breed participating must be completed. This will be accomplished be requesting samples from the past years top winners, best of breeds, and distinguish merits. A strong effort will be placed on acquiring Tonkinese and Bombay samples. Once the collection is complete, the microsatellite marker screening will be extended from 10 to 30 different markers. These data will assist in the evaluation of the size of the Burmese gene pools relative to other breeds and to which of these breeds may be the most useful in extending a gene pool. Deformed kittens will continually be collected. Adult siblings and outstanding parental samples must be acquired. Specific breeders will be contacted for these samples. Genotyping of the cats involved with litters which have produced a deformity will commence. We will proceed with typing microsatellites until a marker for the deformity can be identified. The limitation in success of the project is no longer the need for samples, but could be the number of microsatellites available. Genotyping of the deformed kittens has begun and homozygosity mapping will be used to help determine a marker for the deformity. Typing of all the microsatellites should be completed within the next 12-18 months, thus a markers could be identified if one or more of the microsatellites are in a close proximity to the gene for the defect.

Budget

Typing of 300 microsatellites in 30+ samples and parents. $15,000

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