Lethal white syndrome
Encyclopedia
Lethal white syndrome also called overo
lethal white syndrome (OLWS), lethal white overo (LWO), and overo lethal white foal syndrome (OLWFS), is an autosomal
genetic disorder
most prevalent in the American Paint Horse
. Affected foal
s are born after the full 11-month gestation
and externally appear normal, though they have all-white or nearly all-white coats and blue eyes. However, internally, these foals have a nonfunctioning colon
. Within a few hours, signs of colic
appear and affected foals die within a few days. Because the death is often painful, such foals often are humanely euthanized
once identified. The disease is particularly devastating for breeders
because foals are born seemingly healthy after being carried to full term.
The disease has a similar etiology
to Hirschsprung's disease
in humans. A mutation in the middle of the endothelin receptor type B
(EDNRB) gene
causes lethal white syndrome when homozygous. Carriers, who are heterozygous, that is, have one copy of the mutated allele
, but themselves are healthy, can now be reliably identified with a DNA test. Both parents must be carriers of one copy of the LWS allele in order for an affected foal to be born.
Horses that are heterozygous for the gene that causes lethal white syndrome often exhibit a spotted coat color pattern
commonly known as "frame" or "frame overo." Coat color alone does not always indicate the presence of LWS or carrier status, however. The frame pattern may be minimally expressed or masked by other spotting patterns. There also are different genetic mechanisms which produce healthy white
foals and have no connection to LWS; another reason for genetic testing of potential breeding stock. Though there is no treatment or cure for LWS foals, a white foal without LWS that appears ill may have a treatable condition.
, which may result in premature births, stillborn, or weak foals, foals born with lethal white syndrome appear to be fully formed and normal. The coat is entirely or almost entirely pure white with underlying unpigmented pink skin. Pigmented regions may be any color, and if present are most common around the muzzle, underside of the barrel, and the hindquarters or tail. The eyes are blue. A few lethal white foals have been shown to be deaf.
Healthy foals pass meconium
, the first stool
, soon after birth, though some healthy foals may require an enema
to assist this process. But the meconium of LWS foals is impacted high in the intestine, and never appears, even with the use of enemas. Symptoms of colic
begin to appear within the first day, and all LWS-afflicted foals die within the first few days of life. The painful and inevitable death that follows usually prompts veterinarians and owners to euthanize foals suspected of having lethal white syndrome.
Death is caused by an underdeveloped part of the digestive system. The large intestine of the horse is a complex system where most digestion takes place, and comprises the cecum
, the colon
, and the rectum
. Necropsies on lethal white syndrome foals reveal a pale, underdeveloped colon and intestinal obstruction (impaction). Samples of affected tissue show a lack of nerves that allow the intestine to move material through the digestive system, a condition called intestinal
agangliosis
.
Closer examination of the skin and hair shows both to be unpigmented, and most hair follicles are inactive and many are devoid of hair altogether. All Lethal White Syndrome foals test homozygous for a genetic abnormality.
nerve cells
- are termed pleiotropic. The unusual instance of pleiotropy in LWS foals suggested early on that the syndrome was related to an important section of embryonic tissue called the neural crest
. As the name suggests, the stem cell
s of the neural crest are precursors to nerve cells. Another cell type that descends from neural crest cells are melanocyte
s, pigment-producing cells found in hair follicles and skin. The migration of nerve- and melanocyte-precursors from the top of the embryo to their eventual destinations is carefully controlled by regulatory genes.
Such regulatory genes include endothelin receptor type B
(EDNRB). A mutation in the middle of the EDNRB gene, Ile118Lys, causes lethal white syndrome. In this mutation, a "typo" in the DNA
mistakes isoleucine
for lysine
. The resulting EDNRB protein is unable to fulfill its role in the development of the embryo, limiting the migration of the melanocyte and enteric neuron precursors.
In the case of LWS, a single copy of the EDNRB mutation, the heterozygous state, produces an identifiable trait, but with a very different outcome from the homozygous state.
To produce a foal with lethal white syndrome, both parents must be heterozygotes or carriers of the mutated gene. Without genetic testing, some carriers are misidentified as having white markings due to another gene, while some are even classified as solids.
The presence of this gene in a variety of horse populations in North America
suggests that the mutation occurred in early American history, perhaps in a Spanish-type horse.
gene - carriers of lethal white syndrome - usually exhibit a white-spotting
pattern called "frame," or "frame overo
." Frame is characterized by jagged, sharply defined, horizontally oriented white patches that run horizontally along the horse's neck, shoulder, flank, and hindquarters. The frame pattern by itself does not produce white markings that cross the back, or affect the legs or tail. It does, however, often produce bald faces
and blue eyes. The term "frame" describes the effect of viewing a frame-patterned horse from the side: the white markings appear to be "framed" by a dark-colored border. To date, animals who are heterozygous carriers do not exhibit health concerns associated with carrier-only status. Natural processes of DNA repair
are likely responsible for weeding out EDNRB protein
s made from the mutated instructions.
Not all horses with the heterozygous mutation exactly fit the standard visual description. A horse with the Ile118Lys mutation on EDNRB that is not readily identified as frame-patterned is called a cryptic frame. In addition to cryptic frames, a significant proportion of horses with the frame phenotype
are visually misidentified, even in clinical settings. One study found from a group of visually inspected registered Paints, 18% of breeding stock solids and 35% of bald-faced horses were actually frames. On the other hand, over one quarter of Paints registered in the "overo" category were not frames, and conversely, 10% of horses registered as tobiano also carried frame genetics. The difficulty in accurately identifying frames has contributed to the accidental breeding of Lethal White Syndrome foals.
Minimally marked horses heterozygous for the Ile118Lys mutation are not uncommon: one DNA-tested Thoroughbred
has white markings
limited to a bottom-heavy blaze and two socks below the knee. A Quarter Horse
mare tested positive for the gene after she and a frame Paint stallion produced a Lethal White Syndrome foal; the mare's markings were a thin blaze with a disconnected white spot in the right nostril, with no other white markings. One major study identified two Miniature horse
s that were completely unmarked, but were positive for the Ile118Lys gene.
There are multiple theories for this. Variability in the percentage of individuals with a specific genotype that express an associated phenotype
is called penetrance
, and this may simply be evidence of variable penetrance. Several research groups have suggested that other, "suppressor" genes may limit the expression of frame-pattern white spotting.
On the other end of the spectrum, some white-spotted horses are so extensively marked that the character of the frame pattern is masked. In particular, the tobiano
pattern, a dominant gene, is epistatic
to overo. Other white-spotting genes include splashed white
or "splash," sabino
, and "calico." Any combination, or all, of these white-spotting genes can act together to produce horses with so much white that the presence of frame cannot be determined without a DNA test.
Ambiguous terminology has also contributed to the confusion surrounding this disease. Currently, the American Paint Horse Association
(APHA) categorizes horses as tobiano
, solid, "overo," and tovero
. The association breaks down "overo" into three categories: Frame, Splash
and Sabino
. In the past, "overo" was used even more loosely, to refer to spotted animals that were "Paint, but not tobiano." However, no fewer than four—and likely many more--genetically distinct patterns are included under the term "overo." To be categorized as "overo" by the APHA, a horse must fit a written description: white spotting does not cross the back, at least one solid-colored leg, solid tail, face markings, and irregular, scattered, or splashy white patches. To further complicate matters, various Sabino patterns also appear in some horse breeds that do not carry genetics for frame or any other spotting pattern.
Likewise, official classification of a horse as an unspotted solid is based not on genetic testing, but on a visual description. Horses carrying genetics for frame and other white-spotting patterns may be so minimally marked as to lack the registry's minimum requirements for white. This helps to account for allegedly solid horses producing spotted offspring, called cropout
s.
The long-standing practice of categorizing Paint horses in this manner contributed to the incorporation of the word "overo" into some of the titles used to describe the disease, such as Overo Lethal White Foal Syndrome. However, "overo" is a term that applies to several genetically unrelated white-spotting patterns, and only the frame pattern is indicative of the syndrome. The confusion about the nature of LWS is then furthered by statements such as "there are many overos that do not carry the lethal allele," which is technically correct, but only because the term "overo" also encompasses splash and sabino patterns as well as frame.
gene have lethal white syndrome. In any crossing of two carrier parents, there is a 25% statistical probability of producing a solid-colored, living foal; a 50% chance for a frame-patterned, living foal; and a 25% chance of a LWS foal.
The statistic likelihood of producing a living, frame-patterned foal by crossing two frames is 1 in 2, or 50%; the same odds of producing a living, frame-patterned foal from a frame-to-non-frame breeding which carries no risk of producing a lethal white syndrome foal. Therefore, breeding two frame overos conveys no benefit to breeders hoping to produce another frame overo.
", by definition, applies only to recessive conditions. However, if the frame pattern trait is included in the lethal white syndrome, inheritance of the trait follows an incomplete dominant pattern. It should be noted that the concept of "recessive" and "dominant" predate molecular biology
and technically apply only to traits, not to genes themselves. In pleiotropic
conditions, such as lethal white syndrome, the application of "recessive" or "dominant" can be ambiguous.
A separate issue is the nomenclature applied to the frame pattern itself. While it follows a dominant pattern of inheritance, deviances occur. The majority of horses with the Ile118Lys mutation do exhibit the recognizable frame pattern, but a small percentage are too modestly marked to be classified as "spotted" by breed registries. Such "solid" horses, bred to a solid partner, can produce classically marked frames. The "crop-out" phenomenon can make frame appear to follow a recessive mode of inheritance.
, but occurs in any breed that may carry frame genetics, including American Quarter Horse
s, Appaloosa
s, Thoroughbred
s, Morgan horse
s, Miniature horse
s, Tennessee Walking Horses and Mustang
s, as well as horses that are descended from these breeds. Only two Morgan horses have been identified as frame overos. Breeds that do not carry genes for the frame pattern also do not carry LWS.
Foals affected with lethal white syndrome are not the only white, blue-eyed horses. There are other genes that produce healthy pink-skinned, blue-eyed horses with a white or very light cream-colored coat. For a time, some of these completely white horses were called "Living Lethals," but this is a misnomer
. Before reliable information and the DNA test were available to breeders, perfectly healthy, white-coated, blue-eyed foals were sometimes euthanized for fear they were lethal whites, an outcome which can be avoided today with testing and a better understanding of coat color genetics. The availability of testing also allows a breeder to determine if a white-coated, blue-eyed foal that becomes ill is an LWS foal that requires euthanasia or a non-LWS foal with a simple illness that may be successfully treated.
(HSCHR) in humans, which is also caused by mutations on the EDNRB gene. Various polymorphisms
on this gene result in intestinal agangliosis, in some cases attended by unusual pigmentation of the skin and eyes, and deafness. The occasionally attendant pigmentation condition in humans is called Waardenburg-Shah syndrome
.
The terms "piebald-lethal" and "spotting lethal" apply to similar conditions in mice and rats respectively, both caused by mutations on the EDNRB gene. Only lethal in the homozygous state, the mutations are associated with white-spotted coats, deafness, and megacolon caused by intestinal agangliosis.
Overo
Overo refers to several genetically unrelated pinto coloration patterns of white-over-dark body markings in horses, and is a term used by the American Paint Horse Association to classify a set of pinto patterns that are not Tobiano...
lethal white syndrome (OLWS), lethal white overo (LWO), and overo lethal white foal syndrome (OLWFS), is an autosomal
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
most prevalent in the American Paint Horse
American Paint Horse
The American Paint Horse is a breed of horse that combines both the conformational characteristics of a western stock horse with a pinto spotting pattern of white and dark coat colors. Developed from a base of spotted horses with Quarter Horse and Thoroughbred bloodlines, the American Paint Horse...
. Affected foal
Foal
A foal is an equine, particularly a horse, that is one year old or younger. More specific terms are colt for a male foal and filly for a female foal, but these terms are used until the horse is age three or four. When the foal is nursing from its dam , it may also be called a suckling...
s are born after the full 11-month gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
and externally appear normal, though they have all-white or nearly all-white coats and blue eyes. However, internally, these foals have a nonfunctioning colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
. Within a few hours, signs of colic
Horse colic
Colic in horses is defined as abdominal pain, but it is a clinical sign rather than a diagnosis. The term colic can encompass all forms of gastrointestinal conditions which cause pain as well as other causes of abdominal pain not involving the gastrointestinal tract. The most common forms of colic...
appear and affected foals die within a few days. Because the death is often painful, such foals often are humanely euthanized
Animal euthanasia
Animal euthanasia is the act of putting to death painlessly or allowing to die, as by withholding extreme medical measures, an animal suffering from an incurable, especially a painful, disease or condition. Euthanasia methods are designed to cause minimal pain and distress...
once identified. The disease is particularly devastating for breeders
Horse breeding
Horse breeding is reproduction in horses, and particularly the human-directed process of selective breeding of animals, particularly purebred horses of a given breed. Planned matings can be used to produce specifically desired characteristics in domesticated horses...
because foals are born seemingly healthy after being carried to full term.
The disease has a similar etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
to Hirschsprung's disease
Hirschsprung's disease
Hirschsprung's disease , or congenital aganglionic megacolon is a serious medical problem where the enteric nervous system is missing from the end of the bowel. The enteric nervous system is a complex network of neurons and glia that controls most aspects of intestinal function...
in humans. A mutation in the middle of the endothelin receptor type B
Endothelin receptor type B
Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the EDNRB gene.- Function :Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three...
(EDNRB) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
causes lethal white syndrome when homozygous. Carriers, who are heterozygous, that is, have one copy of the mutated allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
, but themselves are healthy, can now be reliably identified with a DNA test. Both parents must be carriers of one copy of the LWS allele in order for an affected foal to be born.
Horses that are heterozygous for the gene that causes lethal white syndrome often exhibit a spotted coat color pattern
Equine coat color
Horses exhibit a diverse array of coat colors and distinctive markings. A specialized vocabulary has evolved to describe them.While most horses remain the same color throughout life, a few, over the course of several years, will develop a different coat color from that with which they were born...
commonly known as "frame" or "frame overo." Coat color alone does not always indicate the presence of LWS or carrier status, however. The frame pattern may be minimally expressed or masked by other spotting patterns. There also are different genetic mechanisms which produce healthy white
White (horse)
White horses are born white and stay white throughout their life. White horses may have brown, blue, or hazel eyes. "True white" horses, especially those that carry one of the dominant white genes, are rare...
foals and have no connection to LWS; another reason for genetic testing of potential breeding stock. Though there is no treatment or cure for LWS foals, a white foal without LWS that appears ill may have a treatable condition.
Clinical signs
Unlike some coat color dilution lethalsLavender Foal Syndrome
Lavender Foal Syndrome , also called Coat Color Dilution Lethal is a genetic disease that affects newborn foals of Arabian horse bloodlines. Cases reported in peer-reviewed veterinary literature are entirely of foals descended from a number of "Egyptian Arabian" or Egyptian-related bloodline groups...
, which may result in premature births, stillborn, or weak foals, foals born with lethal white syndrome appear to be fully formed and normal. The coat is entirely or almost entirely pure white with underlying unpigmented pink skin. Pigmented regions may be any color, and if present are most common around the muzzle, underside of the barrel, and the hindquarters or tail. The eyes are blue. A few lethal white foals have been shown to be deaf.
Healthy foals pass meconium
Meconium
Meconium is the earliest stools of an infant. Unlike later feces, meconium is composed of materials ingested during the time the infant spends in the uterus: intestinal epithelial cells, lanugo, mucus, amniotic fluid, bile, and water. Meconium is almost sterile, unlike later feces, is viscous and...
, the first stool
Feces
Feces, faeces, or fæces is a waste product from an animal's digestive tract expelled through the anus or cloaca during defecation.-Etymology:...
, soon after birth, though some healthy foals may require an enema
Enema
An enema is the procedure of introducing liquids into the rectum and colon via the anus. The increasing volume of the liquid causes rapid expansion of the lower intestinal tract, often resulting in very uncomfortable bloating, cramping, powerful peristalsis, a feeling of extreme urgency and...
to assist this process. But the meconium of LWS foals is impacted high in the intestine, and never appears, even with the use of enemas. Symptoms of colic
Horse colic
Colic in horses is defined as abdominal pain, but it is a clinical sign rather than a diagnosis. The term colic can encompass all forms of gastrointestinal conditions which cause pain as well as other causes of abdominal pain not involving the gastrointestinal tract. The most common forms of colic...
begin to appear within the first day, and all LWS-afflicted foals die within the first few days of life. The painful and inevitable death that follows usually prompts veterinarians and owners to euthanize foals suspected of having lethal white syndrome.
Death is caused by an underdeveloped part of the digestive system. The large intestine of the horse is a complex system where most digestion takes place, and comprises the cecum
Cecum
The cecum or caecum is a pouch, connecting the ileum with the ascending colon of the large intestine. It is separated from the ileum by the ileocecal valve or Bauhin's valve, and is considered to be the beginning of the large intestine. It is also separated from the colon by the cecocolic...
, the colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
, and the rectum
Rectum
The rectum is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long...
. Necropsies on lethal white syndrome foals reveal a pale, underdeveloped colon and intestinal obstruction (impaction). Samples of affected tissue show a lack of nerves that allow the intestine to move material through the digestive system, a condition called intestinal
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
agangliosis
Ganglion
In anatomy, a ganglion is a biological tissue mass, most commonly a mass of nerve cell bodies. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
.
Closer examination of the skin and hair shows both to be unpigmented, and most hair follicles are inactive and many are devoid of hair altogether. All Lethal White Syndrome foals test homozygous for a genetic abnormality.
Inheritance and expression
Genetic conditions which affect more than one physical trait - in the case of Lethal White Syndrome, both pigment cells and entericEnteric
Enteric can refer to:* A general term describing something related to or associated with the intestines** Microorganisms that inhabit the intestines are commonly known as enteric bacteria* Enteric nervous system...
nerve cells
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
- are termed pleiotropic. The unusual instance of pleiotropy in LWS foals suggested early on that the syndrome was related to an important section of embryonic tissue called the neural crest
Neural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
. As the name suggests, the stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s of the neural crest are precursors to nerve cells. Another cell type that descends from neural crest cells are melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s, pigment-producing cells found in hair follicles and skin. The migration of nerve- and melanocyte-precursors from the top of the embryo to their eventual destinations is carefully controlled by regulatory genes.
Such regulatory genes include endothelin receptor type B
Endothelin receptor type B
Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the EDNRB gene.- Function :Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three...
(EDNRB). A mutation in the middle of the EDNRB gene, Ile118Lys, causes lethal white syndrome. In this mutation, a "typo" in the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
mistakes isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
for lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
. The resulting EDNRB protein is unable to fulfill its role in the development of the embryo, limiting the migration of the melanocyte and enteric neuron precursors.
In the case of LWS, a single copy of the EDNRB mutation, the heterozygous state, produces an identifiable trait, but with a very different outcome from the homozygous state.
To produce a foal with lethal white syndrome, both parents must be heterozygotes or carriers of the mutated gene. Without genetic testing, some carriers are misidentified as having white markings due to another gene, while some are even classified as solids.
The presence of this gene in a variety of horse populations in North America
North America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
suggests that the mutation occurred in early American history, perhaps in a Spanish-type horse.
Heterozygotes
Horses heterozygous for the Ile118Lys mutation on the equine endothelin receptor type BEndothelin receptor type B
Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the EDNRB gene.- Function :Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three...
gene - carriers of lethal white syndrome - usually exhibit a white-spotting
Pinto horse
A pinto horse has a coat color that consists of large patches of white and any other color. The distinction between "pinto" and "solid" can be tenuous, as so-called "solid" horses frequently have areas of white hair. Various cultures throughout history appear to have selectively bred for pinto...
pattern called "frame," or "frame overo
Overo
Overo refers to several genetically unrelated pinto coloration patterns of white-over-dark body markings in horses, and is a term used by the American Paint Horse Association to classify a set of pinto patterns that are not Tobiano...
." Frame is characterized by jagged, sharply defined, horizontally oriented white patches that run horizontally along the horse's neck, shoulder, flank, and hindquarters. The frame pattern by itself does not produce white markings that cross the back, or affect the legs or tail. It does, however, often produce bald faces
Horse markings
Markings on horses usually are distinctive white areas on an otherwise dark base coat color. Most horses have some markings, and they help to identify the horse as a unique individual. Markings are present at birth and do not change over the course of the horse's life...
and blue eyes. The term "frame" describes the effect of viewing a frame-patterned horse from the side: the white markings appear to be "framed" by a dark-colored border. To date, animals who are heterozygous carriers do not exhibit health concerns associated with carrier-only status. Natural processes of DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
are likely responsible for weeding out EDNRB protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s made from the mutated instructions.
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
are visually misidentified, even in clinical settings. One study found from a group of visually inspected registered Paints, 18% of breeding stock solids and 35% of bald-faced horses were actually frames. On the other hand, over one quarter of Paints registered in the "overo" category were not frames, and conversely, 10% of horses registered as tobiano also carried frame genetics. The difficulty in accurately identifying frames has contributed to the accidental breeding of Lethal White Syndrome foals.
Minimally marked horses heterozygous for the Ile118Lys mutation are not uncommon: one DNA-tested Thoroughbred
Thoroughbred
The Thoroughbred is a horse breed best known for its use in horse racing. Although the word thoroughbred is sometimes used to refer to any breed of purebred horse, it technically refers only to the Thoroughbred breed...
has white markings
Horse markings
Markings on horses usually are distinctive white areas on an otherwise dark base coat color. Most horses have some markings, and they help to identify the horse as a unique individual. Markings are present at birth and do not change over the course of the horse's life...
limited to a bottom-heavy blaze and two socks below the knee. A Quarter Horse
American Quarter Horse
The American Quarter Horse is an American breed of horse that excels at sprinting short distances. Its name came from its ability to outdistance other breeds of horses in races of a quarter mile or less; some individuals have been clocked at speeds up to 55 mph...
mare tested positive for the gene after she and a frame Paint stallion produced a Lethal White Syndrome foal; the mare's markings were a thin blaze with a disconnected white spot in the right nostril, with no other white markings. One major study identified two Miniature horse
Miniature horse
Miniature horses are found in many nations, particularly in Europe and the Americas. The designation of miniature horse is determined by the height of the animal, which, depending on the particular breed registry involved, is usually less than as measured at the last hairs of the mane, which are...
s that were completely unmarked, but were positive for the Ile118Lys gene.
There are multiple theories for this. Variability in the percentage of individuals with a specific genotype that express an associated phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
is called penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
, and this may simply be evidence of variable penetrance. Several research groups have suggested that other, "suppressor" genes may limit the expression of frame-pattern white spotting.
On the other end of the spectrum, some white-spotted horses are so extensively marked that the character of the frame pattern is masked. In particular, the tobiano
Tobiano
Tobiano is a spotted color pattern commonly seen in Pinto horses, produced by a dominant gene. The tobiano gene produces white-haired, pink-skinned patches on a base coat color. The coloration is present from birth and does not change throughout the horse's lifetime, unless the horse also carries...
pattern, a dominant gene, is epistatic
Epistasis
In genetics, epistasis is the phenomenon where the effects of one gene are modified by one or several other genes, which are sometimes called modifier genes. The gene whose phenotype is expressed is called epistatic, while the phenotype altered or suppressed is called hypostatic...
to overo. Other white-spotting genes include splashed white
Splashed white
Splashed white or splash is a horse coat color pattern that produces pink-skinned, white markings. Many splashed whites have very modest markings, while others have the distinctive "dipped in white paint" pattern. Blue eyes are a hallmark of the pattern, and splash may account for otherwise "solid"...
or "splash," sabino
Sabino horse
Sabino is a group of white spotting patterns in horses that affect the skin and hair. A wide variety of irregular color patterns are accepted as sabino. In the strictest sense, "sabino" refers to the white patterns produced by the Sabino 1 gene, for which there is a DNA test...
, and "calico." Any combination, or all, of these white-spotting genes can act together to produce horses with so much white that the presence of frame cannot be determined without a DNA test.
American Paint Horse Association
The American Paint Horse Association is a breed registry for the American Paint Horse. It is currently headquartered in Fort Worth, Texas. It was founded in 1965 with the merging of two different color breed registries that had been formed to register pinto-colored horses of Quarter Horse bloodlines...
(APHA) categorizes horses as tobiano
Tobiano
Tobiano is a spotted color pattern commonly seen in Pinto horses, produced by a dominant gene. The tobiano gene produces white-haired, pink-skinned patches on a base coat color. The coloration is present from birth and does not change throughout the horse's lifetime, unless the horse also carries...
, solid, "overo," and tovero
Tovero
The Tovero coloration is a mix of tobiano and overo colorations in Pinto horses and American Paint Horses. The genetics of pinto coloration are not always fully understood, and some horses have a combination of patterns that does not fit cleanly in either category.Some characteristics of a Tovero...
. The association breaks down "overo" into three categories: Frame, Splash
Splashed white
Splashed white or splash is a horse coat color pattern that produces pink-skinned, white markings. Many splashed whites have very modest markings, while others have the distinctive "dipped in white paint" pattern. Blue eyes are a hallmark of the pattern, and splash may account for otherwise "solid"...
and Sabino
Sabino horse
Sabino is a group of white spotting patterns in horses that affect the skin and hair. A wide variety of irregular color patterns are accepted as sabino. In the strictest sense, "sabino" refers to the white patterns produced by the Sabino 1 gene, for which there is a DNA test...
. In the past, "overo" was used even more loosely, to refer to spotted animals that were "Paint, but not tobiano." However, no fewer than four—and likely many more--genetically distinct patterns are included under the term "overo." To be categorized as "overo" by the APHA, a horse must fit a written description: white spotting does not cross the back, at least one solid-colored leg, solid tail, face markings, and irregular, scattered, or splashy white patches. To further complicate matters, various Sabino patterns also appear in some horse breeds that do not carry genetics for frame or any other spotting pattern.
Likewise, official classification of a horse as an unspotted solid is based not on genetic testing, but on a visual description. Horses carrying genetics for frame and other white-spotting patterns may be so minimally marked as to lack the registry's minimum requirements for white. This helps to account for allegedly solid horses producing spotted offspring, called cropout
Cropout
A cropout, crop-out or crop out is a horse with body spots, including pinto or appaloosa spotting, or "high white" horse markings, with a sire and dam who both appeared to have been solid-colored. There are several variations in the definition, depending on the breed registry involved. There are...
s.
The long-standing practice of categorizing Paint horses in this manner contributed to the incorporation of the word "overo" into some of the titles used to describe the disease, such as Overo Lethal White Foal Syndrome. However, "overo" is a term that applies to several genetically unrelated white-spotting patterns, and only the frame pattern is indicative of the syndrome. The confusion about the nature of LWS is then furthered by statements such as "there are many overos that do not carry the lethal allele," which is technically correct, but only because the term "overo" also encompasses splash and sabino patterns as well as frame.
Homozygotes
Homozygotes for the Ile118Lys mutation on the equine endothelin receptor type BEndothelin receptor type B
Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the EDNRB gene.- Function :Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three...
gene have lethal white syndrome. In any crossing of two carrier parents, there is a 25% statistical probability of producing a solid-colored, living foal; a 50% chance for a frame-patterned, living foal; and a 25% chance of a LWS foal.
Producing frame color patterns without producing lethal white
Spotted coat colors, including frame, are popular and sought after by breeders. While many lethal white syndrome foals are accidentally produced when breeders cross two untested cryptic frames, or a known frame and a cryptic frame, some are produced by the intentional breeding of two known frames, whether out of ignorance or indifference. Producing a foal with lethal white syndrome is now completely avoidable. This is because most major animal genetics labs now offer the DNA test for LWS. Whether a horse visually appears to have the frame pattern or not, testing horses of frame or "overo" lineage is highly recommended.The statistic likelihood of producing a living, frame-patterned foal by crossing two frames is 1 in 2, or 50%; the same odds of producing a living, frame-patterned foal from a frame-to-non-frame breeding which carries no risk of producing a lethal white syndrome foal. Therefore, breeding two frame overos conveys no benefit to breeders hoping to produce another frame overo.
Dominant or recessive?
Lethal white syndrome has been described by researchers as both dominantly-inherited and recessively inherited. Lethal white syndrome can be described as recessive because heterozygotes (written Oo or N/O) are not affected by intestinal agangliosis. The term "carrierGenetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
", by definition, applies only to recessive conditions. However, if the frame pattern trait is included in the lethal white syndrome, inheritance of the trait follows an incomplete dominant pattern. It should be noted that the concept of "recessive" and "dominant" predate molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
and technically apply only to traits, not to genes themselves. In pleiotropic
Pleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...
conditions, such as lethal white syndrome, the application of "recessive" or "dominant" can be ambiguous.
A separate issue is the nomenclature applied to the frame pattern itself. While it follows a dominant pattern of inheritance, deviances occur. The majority of horses with the Ile118Lys mutation do exhibit the recognizable frame pattern, but a small percentage are too modestly marked to be classified as "spotted" by breed registries. Such "solid" horses, bred to a solid partner, can produce classically marked frames. The "crop-out" phenomenon can make frame appear to follow a recessive mode of inheritance.
Prevalence
The gene for lethal white syndrome is most common in the American Paint HorseAmerican Paint Horse
The American Paint Horse is a breed of horse that combines both the conformational characteristics of a western stock horse with a pinto spotting pattern of white and dark coat colors. Developed from a base of spotted horses with Quarter Horse and Thoroughbred bloodlines, the American Paint Horse...
, but occurs in any breed that may carry frame genetics, including American Quarter Horse
American Quarter Horse
The American Quarter Horse is an American breed of horse that excels at sprinting short distances. Its name came from its ability to outdistance other breeds of horses in races of a quarter mile or less; some individuals have been clocked at speeds up to 55 mph...
s, Appaloosa
Appaloosa
The Appaloosa is a horse breed best known for its colorful leopard-spotted coat pattern. There is a wide range of body types within the breed, stemming from the influence of multiple breeds of horses throughout its history. Each horse's color pattern is genetically the result of various spotting...
s, Thoroughbred
Thoroughbred
The Thoroughbred is a horse breed best known for its use in horse racing. Although the word thoroughbred is sometimes used to refer to any breed of purebred horse, it technically refers only to the Thoroughbred breed...
s, Morgan horse
Morgan horse
The Morgan is one of the earliest horse breeds developed in the United States. Tracing back to the stallion Figure, later named Justin Morgan after his best-known owner, the breed excels in many disciplines, and is known for its versatility....
s, Miniature horse
Miniature horse
Miniature horses are found in many nations, particularly in Europe and the Americas. The designation of miniature horse is determined by the height of the animal, which, depending on the particular breed registry involved, is usually less than as measured at the last hairs of the mane, which are...
s, Tennessee Walking Horses and Mustang
Mustang (horse)
A Mustang is a free-roaming horse of the North American west that first descended from horses brought to the Americas by the Spanish. Mustangs are often referred to as wild horses, but there is intense debate over terminology...
s, as well as horses that are descended from these breeds. Only two Morgan horses have been identified as frame overos. Breeds that do not carry genes for the frame pattern also do not carry LWS.
Lethal white mimics
Misnomer
A misnomer is a term which suggests an interpretation that is known to be untrue. Such incorrect terms sometimes derive their names because of the form, action, or origin of the subject becoming named popularly or widely referenced—long before their true natures were known.- Sources of misnomers...
. Before reliable information and the DNA test were available to breeders, perfectly healthy, white-coated, blue-eyed foals were sometimes euthanized for fear they were lethal whites, an outcome which can be avoided today with testing and a better understanding of coat color genetics. The availability of testing also allows a breeder to determine if a white-coated, blue-eyed foal that becomes ill is an LWS foal that requires euthanasia or a non-LWS foal with a simple illness that may be successfully treated.
- Double-cream dilutesCream geneThe cream gene is responsible for a number of horse coat colors. Horses that have the cream gene in addition to a base coat color that is chestnut will become palomino if they are heterozygous, having one copy of the cream gene, or cremello, if they are homozygous. Similarly, horses with a bay...
such as cremellos, perlinos, and smoky creams, have cream-colored coats, blue eyes and pink skin. The faint cream pigmentation of their coats can be distinguished from the unpigmented white markings and underlying unpigmented pink skin. A similar-looking "pseudo double dilute" can be produced with help from the Pearl genePearl geneThe Pearl gene, also known as the "Barlink factor," is a dilution gene that somewhat resembles the cream gene and the champagne gene, but is neither. It is a somewhat rare dilution gene found in the American Quarter Horse, American Paint Horse, and Peruvian Paso. The same mutation appears in...
or "Barlink factor" or the Champagne geneChampagne geneThe champagne gene is a simple dominant allele responsible for a number of rare horse coat colors. The most distinctive traits of horses with the champagne gene are the hazel eyes and pinkish, freckled skin, which are bright blue and bright pink at birth, respectively...
. - The combination of tobianoTobianoTobiano is a spotted color pattern commonly seen in Pinto horses, produced by a dominant gene. The tobiano gene produces white-haired, pink-skinned patches on a base coat color. The coloration is present from birth and does not change throughout the horse's lifetime, unless the horse also carries...
with other white spotting patterns can produce nearly white horses, which may have blue eyes. - Sabino horseSabino horseSabino is a group of white spotting patterns in horses that affect the skin and hair. A wide variety of irregular color patterns are accepted as sabino. In the strictest sense, "sabino" refers to the white patterns produced by the Sabino 1 gene, for which there is a DNA test...
s that are Homozygous for the Sabino-1 (Sb-1) gene are often called "Sabino-white," and are all- or nearly all-white. Not all Sabino horses carry Sb-1. - Dominant whiteWhite (horse)White horses are born white and stay white throughout their life. White horses may have brown, blue, or hazel eyes. "True white" horses, especially those that carry one of the dominant white genes, are rare...
genetics are not thoroughly understood, but are characterized by all- or nearly all-white coats.
Analogous conditions
From very early genetic research, Lethal white foal syndrome has been compared to Hirschsprung's diseaseHirschsprung's disease
Hirschsprung's disease , or congenital aganglionic megacolon is a serious medical problem where the enteric nervous system is missing from the end of the bowel. The enteric nervous system is a complex network of neurons and glia that controls most aspects of intestinal function...
(HSCHR) in humans, which is also caused by mutations on the EDNRB gene. Various polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
on this gene result in intestinal agangliosis, in some cases attended by unusual pigmentation of the skin and eyes, and deafness. The occasionally attendant pigmentation condition in humans is called Waardenburg-Shah syndrome
Waardenburg syndrome
Waardenburg syndrome Waardenburg syndrome Waardenburg syndrome (also Waardenburg Shah Syndrome, Waardenburg-Klein syndrome, Mende's syndrome II, Van der Hoeve-Halbertsma-Waardenburg syndrome, Ptosis-Epicanthus syndrome, Van der Hoeve-Halbertsma-Gualdi syndrome, Waardenburg type Pierpont,[5] Van...
.
The terms "piebald-lethal" and "spotting lethal" apply to similar conditions in mice and rats respectively, both caused by mutations on the EDNRB gene. Only lethal in the homozygous state, the mutations are associated with white-spotted coats, deafness, and megacolon caused by intestinal agangliosis.
See also
- Pinto horsePinto horseA pinto horse has a coat color that consists of large patches of white and any other color. The distinction between "pinto" and "solid" can be tenuous, as so-called "solid" horses frequently have areas of white hair. Various cultures throughout history appear to have selectively bred for pinto...
- American Paint HorseAmerican Paint HorseThe American Paint Horse is a breed of horse that combines both the conformational characteristics of a western stock horse with a pinto spotting pattern of white and dark coat colors. Developed from a base of spotted horses with Quarter Horse and Thoroughbred bloodlines, the American Paint Horse...
- OveroOveroOvero refers to several genetically unrelated pinto coloration patterns of white-over-dark body markings in horses, and is a term used by the American Paint Horse Association to classify a set of pinto patterns that are not Tobiano...
- TobianoTobianoTobiano is a spotted color pattern commonly seen in Pinto horses, produced by a dominant gene. The tobiano gene produces white-haired, pink-skinned patches on a base coat color. The coloration is present from birth and does not change throughout the horse's lifetime, unless the horse also carries...
- Sabino horseSabino horseSabino is a group of white spotting patterns in horses that affect the skin and hair. A wide variety of irregular color patterns are accepted as sabino. In the strictest sense, "sabino" refers to the white patterns produced by the Sabino 1 gene, for which there is a DNA test...
- Dilution geneDilution geneDilution gene is a popular term for any one of a number of genes that act to create a lighter coat color in living creatures. There are many examples of such genes:-General:...
- Cream geneCream geneThe cream gene is responsible for a number of horse coat colors. Horses that have the cream gene in addition to a base coat color that is chestnut will become palomino if they are heterozygous, having one copy of the cream gene, or cremello, if they are homozygous. Similarly, horses with a bay...
- White (horse)White (horse)White horses are born white and stay white throughout their life. White horses may have brown, blue, or hazel eyes. "True white" horses, especially those that carry one of the dominant white genes, are rare...
- Equine coat color geneticsEquine coat color geneticsEquine coat color genetics determine a horse's coat color. There are many different coat colors possible, but all colors are produced by the action of only a few different genes. The simplest genetic default color of all domesticated horses can be described as either "red" or "non-red", depending...