Genetic Anganglionic Megacolon
Inheritance of Megacolon in "high white" spotted rats
Overview
Megacolon is caused by a mutation in the gene that codes for endothelin receptor type B or EDNRB which belongs to the G-protein-coupled receptor gene family. A 301-bp deletion spanning the exon 1-intron 1 junction of EDNRB gene has been identified in rats who are carriers of the mutated variant of the gene . This deletion causes the genes to no longer function [2]. Mutations of transcriptors Sox-10 and ZFHX1B are also involved [3]. Mutations in endothelin-3, which is a ligand receptor system have also been observed [1]. The dependent interaction of these genes are responsible for coding the migration of neural crest cells from the neuro tube during embryonic development. The gene expresses itself in many types of tissues such as endothelial cells and can be found in the brain, heart, lungs and kidneys [4].
Rats who are suspected to be carrying the potential lethal form (sl/sl) of the autosomal-recessive based gene are known to have markings known as "blaze". These markings consist of a wedge shaped stripe that runs down from the head to the snout. Some rats will exhibit similar features, but with a white variegated spot across the nasal bridge. Rats with heterochromia "odd-eyed" are also known to be associated with carriers of the sl/sl gene. Other phenotypic features include white underbelly markings that run farther up the lateral areas of the body and white patches on the face, belly and feet. While not all high whites will develop megacolon, they are have a higher risk of passing it onto their offspring if allowed to breed [5].
White underbelly markings that run farther up the body. Courtesy of Spoiled Ratten Rattery.
Characteristic blaze and odd-eyed phenotypic traits associated with the sl/sl gene. Courtesy of Spoiled Ratten Rattery.
Variegated spot on the head potentially caused by depigmentation. Courtesy of Spoiled Ratten Rattery.
Migration of neural crest cells gone wrong
Migration of pigment cells from neural crest in the rat embryo after 18 days (adapted from Wendt-Wagener 1961). Courtesy of ratbehavior.org.
Neural crest cell migration from neural tube. Courtesy of ratbehavior.org.
Onset of megacolon
The late onset of megacolon appears in rats who are 2-10 months old. They will exhibit similar symptoms seen in the early onset form of the disease. It often takes longer for the disease to develop and nursing methods have been recommended to keep affected rats as comfortable as possible until the the disease enters into its advanced stage. This includes providing a highly digestible diet, additional food sources that contain water, and by providing daily enemas. Once the disease advances, euthanasia is the best option [7].
Early onset of megacolon. Courtesy of Ratguide.com.
Late onset of megacolon. Courtesy of Ratguide.com.
Necropsy performed on a recently euthanasized rat with late onset (untreated) megacolon. Severe bloating and pressure from the abdominal cavity are observed. Courtesy of Ratguide.com
Breeding Implications
It is important for potential adopters to look at the pedigree of the rat when they are purchasing a "high-white lookalike" to ensure that the rat and their ancestors are not carriers of the sl/sl gene [5]. Many good breeders will show a pedigree tree for both sire and dam as evidence that their rats are bred from a long generation of non-risk varieties of rats.
Pet stores may attempt to buy and breed these unusual rat varieties as a way to make a profit. There are also amateur breeders who may be breeding these types of rats from an unknown line. While these rats have an unusual phenotype, people do not think about the possibility of their animal developing a genetic disorder and may find out the hard way. This isn't good for neither pet owner or pet rat. It takes at least 3 or more generations of breeding to develop non-risk rats derived from variegated, berkshire and dalmatian based lines [5].
Berkshire rat, a variety used to breed non-risk stock. Courtesy of the Dapper Rat.
Dalmatian rat, a variety used to breed non-risk stock. Courtesy of Cama Rattery.
Variegated rat, a variety used to breed non-risk stock. Courtesy of Cama Rattery.
Berkshire Blazed rat bred from non-risk stock. Courtesy of Cama Rattery.
Berkshire blazed rat bred from non-risk stock. Courtesy of Cama Rattery.
Contemporary Issues
Is it ethical to breed highly attractive looking animals without ensuring the line will be genetically healthy? I would say definitely not. How can we breed for both color and health if disease or conditions effect the animal during the latter part of its life, when it's too old to reproduce? Do we risk breeding them during their prime and hope that whatever health issues they have do not get passed on to the next generation?
I see far too many breeders not ask adopters to report any health issues that they may might develop during the adopted animal's life. I've have male rats develop mammary tumors, which is fairly uncommon and often inherited with rat breeding lines. Feedback such as reporting health abnormalities can help breeders access the health of their lines and take steps to improve them their breeding stock and future lines. Genetic testing, which is currently not available for pet rats may also assist breeders in improving their stock.
Work Cited
1. von Boyen, GBT. Dembowski, C. Ehrenreich, H. Krammer, H-J, Suss, A. Wedel, T. 2002. "Abnormalities of the enteric nervous system in heterozygous endothelin B receptor deficient (spotting lethal) rats resembling intestinal neuronal dysplasia." Gut; 51: 414-419.
2. Cass, Daniel T. Gariepy, Cheryl E. Yanagisawa, Masashi. 1996. "Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color." Proc. Natl. Acad. Sci. USA; 93: 867-872.
3. Airey, David C. Bradley, Kevin M. Cantrell Ashley V. Chandler, Ronald L. Owens, Sarah E. Smith, Jefferey R. Southard-Smith, Michelle E. 2004. "Interactions between Sox10 and EdnrBmodulate penetrance and severity of agangionosis in the Sox10Dom mouse model of Hirshsprung disease." Hum. Mol. Genet; 13 (19): 2289-2301.
4. Ikadai, Hiroshi. Karaki, Hideaki. Kumagai, Taeko. Kunieda, Testuo. Ozaki, Tsuyoshi. 1996. "A Mutation in Endothelin-B Receptor Gene Causes Myenteric Aganglionosis and Coat Color Spotting in Rats." DNA Research; 3: 101-105.
5. Brooks, Elizabeth. "High-White and High-Risk." N.p., n.d Web. Accessed 02 May 2013.
<http://spoiledratten.com/highwhitecont.html>.
6. "Rat Health Notes: White Blazes and Megacolon". N.p., n.d. Web. Accessed 02 May 2013.
<http://www.ratbehavior.org/megacolon.htm>.
7. Bunte, RM. Coventry, S. Li, X. Lipman, NS. Wardrip, CL. CS, Yuan. 1998. "Familial megacusum and colon in the rat: a new model of gastrointestinal neuromuscular dysfunction. Laboratory Animal Science; 48: 243-252.
8. Grant, Karen. "Rat Health Guide: Megacolon. N.p., n.d. Web. Accessed 02 May 2013.<http://ratguide.com/health/digestive/megacolon.php>.
9. "H locus and friends." N.p., n.d. Web. Accessed 02 May 2013.