Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 2 Comparative Medical Genetics
of the FVII protein, leaving affected animals with 4% of
normal FVII plasma activity (Callan et al., 2006).
Furthermore, many enzyme functions depend on the
availability of a vitamin or high-energy intermediate compound
(which are also known as cofactors). Therefore,
in addition to those diseases in which a mutation affects
the protein function directly, alterations of the affinity of
an enzyme for the cofactor or impairments in the normal
absorption or conversion to the active form of the required
cofactors can result in dysfunction (see the discussion of
methylmalonic aciduria and cobalamin deficiency, presented
later in this chapter). Of the metabolic disorders,
these are the most amenable to therapeutic interventions
(e.g., parenteral or megadose vitamin supplementation).
Because genetic alterations are possible at any gene
locus, inborn errors of metabolism constitute a large heterogeneous
group of monogenic (and in the future likely
polygenic) disorders. Thus, any mutation affecting the
expression or coding sequence in some way can produce
any of a variety of malfunctions of the mature protein.
Indeed, with the advanced biochemical and molecular
characterization of hereditary disorders, most of the genetic
defects could be considered to be “ inborn errors of metabolism
” including malformations and susceptibility to various
simple and complex disease traits.
c . Genetic Predisposition to Disease
Increased susceptibility to disease has been recognized
more recently to have a genetic basis. Single gene defects
for a variety of genetic predispositions have been identified.
For instance, mutations in the beta chain of the integrin
leukocyte adhesion protein predispose to overwhelming
bacterial infections in red Holstein calves and Irish and
red and white setter puppies (Foureman et al., 2002; Kijias
et al ., 1999; Shuster et al. , 1992 ). A single common mutation
in the ryanodine receptor in various breeds of pigs is
responsible for the development of malignant hyperthermia
(Fujii et al. , 1991 ). A defect in the mutlidrug-resistant gene
1 is responsible for serious adverse drug reactions in collies
and related dog breeds ( Mealey et al. , 2001 ; Neff et al. ,
2004 ). Moreover, predispositions caused by complex/polygenic
traits are being currently characterized and include
common predispositions to infections, inflammation,
immune disorders, degenerative disorders, drug reactions
(pharmacogenetics), and neoplasia.
2 . Inheritance of Genetic Diseases
Genetic diseases are generally produced by defects in
nuclear DNA and only rarely from anomalies in mitochondrial
DNA (maternal pattern of inheritance such as with
some myopathies). In contrast to humans where dominant
traits seem to prevail, hereditary diseases are more often
recessively inherited in domestic animals. Although inbreeding
practices preserve and propagate desirable characteristics
for meat and milk production in food animals or agility,
behavior, and morphological traits in companion animals,
they bear the risk of passing on deleterious mutations to their
offspring and ending up with animals that are homozygous
for the mutant allele and thus affected with a genetic disease.
As there is pressure to increase health, fertility, and productivity
in food animals, deleterious traits are rapidly eliminated
with proper breeding practices. Furthermore, the diagnostic
evaluations and characterizations of genetic diseases
have been facilitated by the recent advances in medicine
and comparative genetics, pet owner’s interest, and financial
support from the National Institutes of Health, other government
sources, and foundations, as these animals may also
serve as models of human disease. However, in companion
animals, breeding is done less scientifically, emphasizing
looks and character, leaving many animals at risk of carrying
mutant alleles that may produce affected offspring in
future generations. Because of these inbreeding practices,
some mutations seem to be surprisingly prevalent in certain
breeds of dogs and cats. Whereas a mutant allele frequency
of 1% is considered to be high in humans, mutant allele frequencies
of 10% have been reported for several diseases
in several breeds of domestic animals, likely because of
founder and popular sire effects. Moreover, X-chromosomal
recessive traits such as hemophilia A and B, dystrophin deficiency,
and X-linked severe combined immunodeficiency
seen in different breeds may result from new mutations in
oocytes and, thus, may well be limited to a particular family.
It is important to recognize that the Mendelian concepts
of dominant and recessive modes of inheritance refer to
the phenotypic presentation of heterozygous and homozygous
animals for a particular trait. With recessive disorders,
the presence of one normal/wild-type allele is sufficient
to assure adequate activity to complete a certain function,
whereas with a dominant trait the presence of one mutant
allele is already deleterious. For instance, mutant and normal
collagen strands will not make a functional fibril for
normal joint, ligament, and skin structure. Furthermore, at
the DNA level any polymorphism or disease-causing mutation
is “ codominant ” and hence the terms dominant and
recessive should be reserved for phenotypes and disorders
and not be used for genes. Finally, it is being noted that single
gene defects can exhibit variations in clinical signs and
disease progression that are likely caused by yet to be determined
modifying genes or environmental factors. Hence,
simply inherited disorders may ultimately be found to have
a more complex metabolic and molecular genetic basis.
3 . Screening for Hereditary Diseases
Genetic screening generally requires more than clinical
physical examination, routine blood and urine tests, and
imaging studies to detect and definitively diagnose animals
with genetic diseases. A variety of specific laboratory tests,
such as hematological, biochemical/metabolic, and DNA