Ultimately, all simply inherited disorders will be understood in biochemical terms. At present, however, there is only a small proportion of inherited diseases for which a biomichal explanation is possible, and these are the subject matter of this chapter. Although simply inherited diseases currently represent only a small proportion of all inherited disorders, they do include some well-known and economically important diseases and hence are worthy of our consideration. A more important reason for studying them is that in learning about known biochemical disorders, we are learning about the basic priciples that in future will be found to determine many other inherited diseases.
All the inherited disorders whose biochemical basis has been identified to date are the result gene mutations. At one extreme, the simplest alteration in polypeptide structure that can result from such a mutation is the substitution of just one amino acid for another at a certain position along the polypeptide chain. At the other extreme, a mutation may render the cell incapable of synthesizing any polypeptide at all. If an altered (mutant) polypeptide is synthesized, the it may be just as effective in its specific biological role as the polypeptide it has replaced. Alternatively, the mutant polypeptide may be unable to carry out its specific function, or may carry out that function with reduced efficiency. Whether a polypeptide is present but unable to act properly, or is completely absent, the end result is the same: there is a deficiency of functional plypeptide and a consequent impairment of the physiological process in which that polypeptide is required. In discussions of biochemical disorders, therefore, whether a molecule is completely absent, or is present in a form that is unable to function properly, it is said to be deficient.
The aim of this chapter is to explain the main types of biochemical disorders that result from deficiencies of polypeptides brought about by mutataion.
3.2. Inborn errors of metabolism.
If a particular polypeptide acts as an enzyme or is part of an enzyme, then a mutation in the relevant gene sometimes result in a deficiency of that enzyme, with a consequent blockage in the relevant biochemical pathway at the point where that enzyme in required. Diseases that result from such blockage are called inborn errors of metabolism. A good example of an inborn error of metabolism in animals is congenital haemolytic anaemia associated with pyruvate kinase deficiency, which has been reported in Basenji and Beagle dogs.
3.2.1. Congenital haemolytic anaemia due to pyruvate kinase deficiency
In this deases, the affected biochemical process in anaerobic glycolisis in red blood cells. The relevant reactions in the pathway are illustrated in Fig 3.1. Il is clear from the pathway diagram that a deficiency of the enzyme pyruvate kinase (PK) will result in decreases glucose utilization, a build-up of intermediates between glucose and phosphopyruvic acid, a deficiency level of anedosine triposphate (ATP) in red blood cells.
Fig 3.1. A portion of the pathway describing anaerobic glycolisis in red blood cells, showing some of the intermediate steps by which glucose (plus adenosine diphosphate, ADP) is converted to lactic acid (plus adenosine triphosphate, ATP which in an important source of energy for red blood cells). The enzyme pyruvate kinase (PK) is required for the conversion of phosphopyruvic acid to pyruvic acid. (After Patterson 1975)
Since ATP is a major source of energy in these cells, the decreased ATP level is an important contributing factor to a decreased life span of red blood cells, and hence to what is seen as congenital haemolytic anaemia. Other clinical signs, many associated with a lack of energy, include syncope during exercise, weakness, excessive sleeping, pallor, tachycardia, splenomegaly, and occasionally orange faeces (Prasse 1997). It is a sobering thought that all these signs have probably resulted from a single base substitution in a DNA molecule. These diverse result of a single mutation provide a good example of pleiotropy, which is the existence of more than one end result from the action of one gene. A gene that influences a variency of characteristics is said to be pleiotropic.
If tests for erythrocytic PK activity are conducted among normal dogs within a population known to have produced animals with congenital haemolytic anaemia, then it is found that in some normal animals, including all those that are parents of affected animals , the level of PK activity is approximately 50 per cent of that observed in the remainder of normal animals. It is also found that those animals with the disease have essentially zero PK activity.
The explanation for these observations is that in affected individuals, both gene responsible for the production of PK are mutants. Affected animals are thus homozygous for the defective gene (dd). Those normal animals with normal PK activity have two normal PK genes (DD), and are thus homozygous for the normal gene. Those normal animals with approximately 50 per cent of normal PK activity are heterozygous (Dd), having one normal gene (producing normal PK) and one defective gene (producing very little or no active PK). Thus the level of PK activity is directly proportional to the number of ‘doses’ of the normal gene.
This is important from a practical point of view, because it provides a means of identifying heterozygotes or carriers.
Obviously, the same conclusion applies to any simply-inherited, autosomal disease provided that the gene product is known and that its quantity or activity can be measured in live animals: carriers can be detected by a simple biochemical test, because they show approximately 50 per cent of normal enzyme activity. As discussed in Chapter 11, the detection of carriers is of major importance in many attempts at controlling genetic diseases.
As well as illustrating carrier detection by biochemical means, inborn errors of metabolism provide good illustrations of other important genetic concepts.
3.2.2. Type of gene action
In the case of congenital haemolytic anaemia discussed above, and many other inborn errors of metabolism, the D allele is said to be completely dominant to the d allele with respect to clinical signs of the disease. Another way of expressing this is to say that d is recessive to D, or that congenital haemolytic anaemia is a recessive disease. More generally, an allele is recessive for any characteristic if its effect with respect to that characteristic is not evident in the heterozygote. Likewise, an allele is dominant with respect to a particular characteristic if its effect is the same in heterozygotes as in homozygotes. Now suppose that the characteristic with which we are concerned is the level of PK activity, rather than clinical signs. In this case, the D allele and the d allele are said to be each co dominant or incompletely dominant, because the heterozygotes exhibits the effect of both alleles. The terms recessive, dominant, co-dominant and incompletely dominant describe specific relationships between alleles, or specific types of gene action. From the above example, it is evident that:
Two allels at one locus can exbibit more than one type of gene action, depending on the characteristic being considered.
3.2.3. Genotype and Phenotype
It is convenient to introduce two more terms at this stage. The first is genotype which refers to the genetical constitution of an individual at one or more loci. Carriers of congenital haemolytic anaemia, for example, have the genotype Dd , while affected animals have the genotype dd. The other terms is phenotype which is an observable characteristic of an individual. In relation to PK activity in congenital haemolytic anaemia, there are three different phenotypes (normal activity, 50 per cent activity and zero activity) corresponding exactly to three respective genotypes (DD, Dd and dd). With respect to clinical signs, however, the same three genotypes give rise to only two phenotypes: both DD and Dd animals are normal while dd animals are affected. There is not always, therefore, a one-to-one relationship between genotypes and phenotypes. In fact, situations in which there is a one-to-one relationship are the exception rather than the rule.
3.2.4 inborn errors of lysosomal catabolism
Other good examples of inborn errors of metabolism are the inherited lysosomal storage diseases that result from defects in lysosomal catabolism. Lysosomes are small membrane-bound organelles found in the cytoplasm. They act as the digestive system system of the cell and thus contain many enzymes which act in a step-wise manner to break down many different, complex molecules into monomeric units of simple lipids, amino acid, monosaccharides and nucleotides. If a particular enzyme is absent or inactive, then the step-wise degradation in halted, with a consequent build-up (storage) in the lysosomes or elsewhere of the material that was to have been broken down by that enzyme. In other words, an inborn error of lysosomal catabolism produces a lysosomal storage disease (jolly and blakemore 1973). Not all lysosomal storage diseases are inherited, and not all inherited lysosomal storage diseases have been identified as owing their origin to an inborn error of lysosomal catabolism. In the following discussion we shall be concerned mainly with those storage diseases that are due to inborn errors of lysosomal catabolism, as they are the best understood.
The formal criteria for a disease to be classified in this category are listed in Table 3.1, while Table 3.2, lists diseases that satisfy these criteria. Although these are potentially many a large number of different storage materials and hence potentially many different signs of disease, most lysosomal storage diseases have certain general clinical signs in common. According to Blakemore (1975), affected animals are usually normal at birth but fail to grow as rapidly as their litter mates or contemporaries ; many of the deseases manifest as neurological disorders in young animals ; the disease is always progressive and has a fatal outcome, and the age of onset and speed of progression are veriable but the two are usually directly related. Histologically, lysosomal storage diseases are characterized by cellular bodies containing the storage substance or, if the storage substance dissolves during histological preparation, by empty vacuoles.
Table 3.1. The formal criteria for disease to be classified as an inborn error of lysosomal catabolism
1. The disease should be a storage disease.
2. It should be simply inherited
3. The storage material, which need not be homogeneous, should be stored at least initially within lysosomes.
4. There should be a partial or absolute deficiency of one of the lysosomal enzymes.
5. This enzyme would normally hydrolyse the storage material.
6. Other enzyme should have noramal or increased activities.
(Adapted from Hers 1965)
The most economically important and extensively studied inborn error of lysosomal catabolism is mannosidosis in cattle. Prior to the introduction of a control programme in 1974 in New Zealand, where it was most prevalent, approximately 3000 Angus calves were affected each year. As it usually produces death within the first year of life, this disease represented a substantial problem to breeders of Angus cattle and especially to owners of herds that happened to have a high incidence of the disease. We shall discuss the result of the New Zealand mannosidosis available for the control of genetic diseases.
The other inherited lysosomal storage disease that we shall consider is Chediak-Higashi disease, an autosomal recessive disease that is reported commonly in milk, and rarely in mice, cats, cattle, killers whales and humans. It is characterized by defective pigmentation leading to partial albinism, anomalous giant granules in leucocytes, an increased susceptibility to disease and premature death (Padgett 1968, 1979).
Table 3.2. Inherited storage diseases due to inborn errors lysosomal catabolism (adapted from Jolly 1977a)
Glycogen storage disease type 11 , pompe’s disease
Cat, dog,sheep, cattle
Domestic Lapland Corriedale Shorthorn
Sandstromm et al (1969)
Monktelow and Hartley (1975)
Howell et al (1981)
Oligosaccarrides containing mannose and N-accetyl-glucosamine
It appears that the giant granules are lysosomes distended because of the storage of an incompletely broken-down lysosome metabolite, as yet unidentified. Unlike many other lysosomal storage diseases, Chediak-Higashi disease is not associated with neurological disturbances. The most interesting aspect of this disease is that it occurs in all mink that are homozygous for a recessive coat colour allele known as Aleutian. The reason for this is that the Aleuutian coat colour, which result in attractive and valuable pelts, is the result of the same defective pigmentation that is part of the clinical signs of Chediak-Higashi disease. Thus in selecting mink for Aleutian coats are sufficiently valuable for the breeders to tolerate the increased susceptibility to disease and early death of the animals that grow them. So serious is the susceptibility to disease that for many years a particular viral disease was seen only in Aleutian mink and in fact became known as Aleutian disease, a name that remains in use today (Porter et al. 1980). Although it is now known that all mink are susceptible to this disease, those mink that are homozygous for the Aleutian allele have a 5 to 8-fold higher mortality to the relevant virus than do other mink.
3.2.5. Porphyria and protoporphyria
Two interesting inborn errors of metabolism are associated with defects in the synthesis of haem. The first of these is porphyria, an autosomal recessive disease due to a deficiency of the enzyme uroporphyrinogen III cosynthetase, which leads to a build-up of the intermediates of haem biosynthesis and a lack of haem itself. This deficiency of haem gives rise to haemolytic anaemia which is one of the signs of the disease. The intermediates in the haem pathway, called poriphyrinogens, are readily oxidized to porphyrins, which are aromatic compounds that absorb visible light and induce photosensitivity. The most common porhyrinogen involved in porphyria is uroporphyrinogen I, which when accumulated in excess, result in a characteristic red staining of teeth, bone and urine. Known as pink-tooth in cattle, this disease has also been observed in cats, pig and humans (Levin 1974). In all of these species it is a rare disease in which heterozygotes have an enzyme activity intermediates between that of normal homozygotes and diseased animals.
In contrast, all fox squirrels (sciurus niger) have extremely low activity of uroporphyrinogen III cosynthetase and hence all have red bones and teeth due to the deposition of excess uroporphyrinogen 1 . However, fox squirrels show neither photosensitivity nor haemolytic anaemia, which indicates that they have developed some physiological means of coping with low activity of uropophyrinogen 3 cosynthetase.
Another enzyme involved in the biosynthesis of haem is ferrochelatase. If this enzyme is absent, or is present with markedly reduced activity, then there is a build-up of protoporphyrins which result in photosensitivity. Unlike porphyria, there is no associated colouration of teeth, bones and urine. The disease,which is called protoporphyria has been reported in cattle (Ruth et al, 1977) and in humans.
The final inborn error of metabolism that we shall consider is a heritable disorder of connective tissue. Some animals are born with easily extendible and very fragile skin, a condition that in sheep (Fjolstad and Helle 1974) and cattle (Hanset and Ansay 1967) is known as dermatosparaxis. In animals suffering from this disease, severe lacerations result from the slightest scratch that in normal animals would cause only slight damage. In sheep and cattle, the cause of this disease is a build-up of an abnormal procollagen due to a deficiency of the enzyme procollagen peptidase. Normal cylindrical collagen fibrils cannot be formed in animals with the disease, and instead the abnormal procollagen forms itself into flattened twisted ribbons. In both sheep and cattle, this disease is inherited as an autosomal recessive condition.
3.2.7. Genetical heterogeneity of disease
A disease with the sme clinical but different histo-pathological signs as dermatosparaxis has been reported in mink and dogs (Hegreberg et al. 1969), and in cats (Patterson and Minor 1977). In these three species, the disease is called cutaneous asthenia, and appears to be inherited as an autosomal dominant condition. However, its biochemical basis in these three species has not yet been identified.
The fact that a specific set of clinical signs can represent more than one disease in terms of inheritance is an indication of genetical heterogeneity of disease.
In sheep, cattle,mink, dogs, and cats the clinical signs are similar: it is only when the biochemical and histo-pathological features are examined as well that at least two different diseases are recognized. The first disease (autosomal recessive in sheep and cattle) involves a deficiency of an enzyme involved in the processing of procollagen, while the second disease (autosomal dominant in mink, dogs, and cats) is characterized by abnormal collagen involved in packing defects in fibrils and fibres, and apparently no enzyme deficiency. The locus for the first disease is the structural gene for an enzyme involved in procollagen processing, while the locus for the second disease is probably the structural gene for collagen itself.
This is an example of genetic heterogeneity between species. Although such heterogeneity can cause confusion from time to time, a far greater source of confusion is genetic heterogencity of disease witbin a species. For example, both forms of the above connective tissue disorder occur in humans.
If a set of clinical signs appears to have a genetic basis, but if genetic heterogencity within a species remains undetected, it will be impossible to establish the exact form of inheritance. Indeed, as long as the heterogeneity remains, the available data will present a most confusing picture of inheritance. Although it is easy to be wise after the event, it is very difficult in practice to ensure that the available data on any syndrome all belong to the one disease entity and hence are homogeneous. Data are more likely to represent genetic homogeneity if they have been obtained from animals that not only present with the same clinical signs, but which also have the same histo-pathological and biochemical lesions as well.
3.3. Type of gene action and type of disease
In the connective tissue diseases described above, two types of gene action have been observed. One disease is inherited as an autosomal recessive condition and is associated with deficiency of an enzyme that processes procollage. The other appears to be inherited as an autosomal dominant condition, and is associated with an abnormal molecule which may be due to mutation of the collagen structural gene.
There are reasonable grounds for expecting recessive diseases to be associated with enzyme deficiencies, and dominant or codominant diseases to be caused by defects in non enzymatic polypeptides.
Inborn errors of metabolism, for example, are inherited as recessive diseases, because enzymes are required in such small quantities that 50 per cent activity in heterozygotes is sufficient for normal functioning. On the other hand, if the mutant polypeptide has, for example a structural role rather than an enzymatic role, then the structures incorporating that polypeptide will be defective in some way, and the heterozygote may well show some form of the disease. This is the most likely explanation currently available for the situation seen with cutaneous asthenia in mink, dogs and cats. It remains to be seen whether further research will substantiate this explanation.
If the polypeptide is a substrate in a particular process or is involved in transport, then a decrease by one-half in the production of normal polypeptide as occurs in heterozygotes might be expected to cause some clinical signs in the heterozygote because, like those with a structural role, polypeptides involved in transport and acting as substrate are also often required in relatively large quantities.
In general, therefore, non-enzymatic polypeptides should lead to dominant or at least incompletely dominant diseases, while enzyme defects should give rise to recessive diseases.
Whether or not this prediction holds for the inherited connective tissue diseases discussed above, there is increasing evidence, mainly from human inherited diseases, that it is quite useful as a general rule. It has certainly been well enough substantiated for there to be general agreement that it is a waste of time to search for an enzymatic deficiency in any disease that is inherited in a dominant manner. Likewise it is generally agreed that a search for enzymatic defects should have high priority in attempts to determine the biochemical basis of recessive diseases.
3.4 Inherited bleeding disorders.
Haemostasis, or the arrest of bleeding, involves the blood vessel wall, blood platelets and coagulation factors. Among the many recognized bleeding disorders are those due to a deficiency in one of the coagulation factors. Table 3.3 lists the coagulation factors for which a simply inherited deficiency disease has been reported in animals. With the exception of haemophilia A and haemophilia B, heterozygotes for the bleeding disorders listed in Table 3.3 often exhibit a mild form of the disease.
In these cases, the types of gene action with respect to the disease is the same as the types of gene action with respect to the coagulation factor activity: the normal and the defective allele are co-dominant or incompletely dominant in terms of the disease and in terms of the biochemical lesion. It is obvious that detection of carriers for these conditions can be based initially on clinical signs, and subsequently confirmed with a coagulation factor assay. Since none of the factors deficient in these diseases is an enzyme, the co-dominant or incompletely dominant pattern of inheritance is consistent with the generalization made in the previous section. However, factors II, VII, IX, X and XI are all precursors of enzymes. We must conclude that the presence of one-half of the normal concentration of enzyme precursor in heterozygotes is not sufficient to prevent some ciinical signs appearing.
Unlike all the other disorders in Table 3.3, haemophilia A and haemophilia B are recessive diseases. Heterozygotes, therefore, exhibit no signs of the disease although they do show a reduced coagulation factor activity. Another interesting aspect of these two diseases is that they are the only two that are x-linked. Because they are x-linked, heterozygotes are seen only in the homogametic sex and there are no carriers of these diseases among the heterogametic sex. Thus in species in which these diseases have been reported, all carries are female.
The differences between the haemophilias on the one hand, and all the other bleeding disorders in Table 3.3 on the other, raise two important questions: why are the haemophilias recessive diseases whdn they appear not to be due to an enzyme deficiency, and how can a deficiency of the one coagulation factor (factor VIII) be inherited in two different ways, with haemophilia A being x-linked and von Willebrand's disease being autosomal? Although there is still much to be understood in this area, clues to the answers to these questions are provided by the fact that the product of the haemophilia A locus is a protein (called factor VIIi procoagulant activity protein or VIIIC) that is involved in regulation of the coagulation cascade, and is required in relatively small quantities. On the other hand, the product of the von Willebrand locus is a protein (called von Willbrand factor protein or VMF) that acts as a carrier of VIIIC, And also plays an important structural role in clot formation; it is required in much larger quantities. The two different forms of inheritance of factor VIII deficiency can be explained by noting that factor VIII is a complex consisting of VWF and VIIIC, with VWF accounting for 99 per cent of the mass of the complex (Zimmerman et al, 1983). The reduced factor VIII activity that is often observed in heterozygotes for these two diseases is probably a consequence of random X-inactivation, which, as we saw in Chapter 1, occurs in all female mammals. In the case of haemophilia, the end result will be that, on average, one half of the cells of a heterozygous female will express the normal allele and thus will produce normal quantities of factor VIII, while the other half of the cells will express the harmful allele, and consequently will fail to produce any factor VIII.
One final point should be noted in this regard. Since inactivation is a random process, not all females will have exactly one half of each type of cell. In fact, a wide range of proportions of the two cell types can occur, from females having most or all cells with the normal allele active, to females having most or all cells with the haemophilia allele active. Female with a large proportion of normal cells may be indistinguishable from those who are homozygous for the normal allele, while females with a low proportion of normal cells may actually exhibit signs of the disease. It is evident that heterozygote detection in such cases is not straightforward. In general:
Heterozygote detection for X-limked recessive biochemical defects is not as effective as for autosomal recessive biochemical defects, because of random X-inactivation.
The final aspect of bleeding disorders that we shall consider is the location of the two X-linked haemophilia loci. In humans, it is known that although both loci are on the X chromosome, the two diseases are inherited independently (unlinked), thus indicating that the two loci are widely separated on the same chromosome. In an attempt to see whether the same was true for dogs, Brinkhous et al. (1973) observed the results of matings involving females that were carriers of both haemophilia A and haemophilia B, having the recessive gene for haemophilia A on one X chromosome and the recessive gene for haemophilia B on the other X chromosome. Since only females have two X chromosomes, it is only in females that crossing-over can occur with respect to the two haemophilia loci. The four possible results of meiosis in such females (two crossover X chromosomes and two non-crossover X chromosomes) are shown in Table 3.4. Each of there four chromosomes is readily recognizable in male offspring of the above carrier females,
Table 3.4. Results of test matings conducted between carrier females and any type of male, in order to determine the linkage relationship between haemophilia A and haemophilia B in dogs.
At each locus, the symbol for the normal (dominant) allele is +. While the recessive alleler for haemophilia A and haemophilia B are indicated by a and b respectively. Since both diseases are X-linked, and since only females have two X chromosomes, crossing-over between the two haemophilia loci can occur only in females. Thus the only chromosomes shown are those from the females used as parents in the test matings. Each of these females was heterozygous at both loci, with the haemophilia alleles being in repulsion, i.e. on different chromosomes:
(Adapted from Brinkhous et al. (1973) "Expression and linkage of genes for X-linked hemophilias A and B in the dog." Blood 41, 577-85. Reprinted by permission of Grune and Stratton, Inc. And the authors.)
The maternal X chromosome is the one inherited from the mother or dam.
irrespective of the genotype of the male parent, since the male off-spring have only one X chromosome. These four chromosomes can also be distinguished in female offspring, so long as the genotype of the male parent is known. The results of the matings described by Brinkhous et al. (1973), are presented in Table 3.4, and clearly indicate that the two haemophilia loci are unlinked in dogs, just as in humans. These results provide yet another confirmation of the generally accepted hypothesis proposed by Ohno (1967, 1973) that the X chromosome has been particularly conservative throughout mammalian evolution, so that the same loci occur in the same position on the X chromosome in most mammalian species.
3.5 Inherited haemoglobin disorders.
Haemoglobin is one of the most intensively studied of all biological molecules. Amino acid sequences have been obtained for haemoglobins from a large number of different species, giving rice to a fascinating picture of evolution. Within many species, different forms of haemoglobin have been identified and, in many cases, explained in terms of several or even just one base substitution in the corresponding DNA. In humans, this work has identified haemoglobins whose function is defective and which give rise to a group of hereditary disorders known as the haemoglobinopathies. The most famous of these is sickle-cell anaemia, whose profound effects were shown in 1956 to be the result of a single substitution of valine for glutamic acid in position 6 of the ~beta~ peptide chain. From the genetic code in Table 1.2, it can be deduced that this substitution must have been due to changing the relevant DNA triplet from CTT to CAT or from CTC to CAC, either of which involves just one base substitution, of adenine for thymine, in the DNA. The second of these alternatives was confirmed in 1977 when the nucleotide sequence of messenger RNA from the normal ~beta~ chain was determined. It was found that glutamic acid in position 6 of the normal ~beta~ chain is encoded by GAG in RNA, and by CTC in the corresponding DNA.
Another group of haemoglobin disorders in humans is known as the thalassemia syndromes. Their main clinical sign is anaemia which is due to reduced or complete absence of production of either ~alpha ~ or ~beta ~ globin. Recent research in this area, using many of the recombinant DNA techniques described in Chapter 2, has been reviewed by Bank et al. (1980). It now appears that the deficiencies in production of ~alpha ~ or ~beta ~ globin are due to deletions of certains nucleotide sequences in the DNA molecules that normally code for the globins, i.e. In the structural genes. Interestingly, some of the anaemias are also associated with deletions in DNA which is normally adjacent to the structural genes (the so-called flanking sequences), thus confirming that flanking sequences play a role in regulation of expression of structural genes.
Although many different haemoglobins have been identified in animals, on examples have been reported to date that involve a sufficient effect in function to result in clinical signs. Similarly, no cases of thalassemia syndrome have been reported in animals. This discrepancy between the situation with humans and with animals reflects the more intensive clinical supervision given to humans, and also the more intensive research effort in humans. There is every reason to believe that haemoglobinopathies will become known in animals as research proceeds in the future.
3.6 Inherited immunodeficiencies.
As described in chapter 8, the immune system of higher animals consists of two main sections: that which gives rise to cell-mediated immunity (concerned with transplantation immunity and delayed hypersensitivity) and that responsible for the production of antibodies. Figure 3.2 is a simplified representation of the immune system and indicates those points at which blockages have occurred, producing inherited immunodeficiencies in animals.
Fig. 3.2. A simplified representation of the immune system, showing points at which blockages are thought to occur in animals, leading to inherited immunodeficiencies.
The most widely studied of such diseases is combined immunodeficiency disease (CID) in Arab horses (Splitter et al. 1980). It is an autosomal recessive disease which appears to be due to a blockage between the stem cells and the lymphoid precursor cells (position 1 in fig. 3.2). As a result. Affected foals lack both T cells and B cells, and hence are unable to mount any form of immune response. Clinical signs include lymphopenia, immunoglobulin efficiency, absence of cell-mediated immunity, thymic hypoplasia and a severe reduction in splenic and lymph node lymphocytes. Consequently, foals show a markedly increased susceptibility to infection, and usually die within 5 months of birth. Infections are usually due to equine adenovirus, although the protozoan pneumocystis carinii or various bacteria have been implicated in a number of deaths.
The biochemical defect resulting in CID is not yet known, but because it is a recessive disorder there is a good chance, as we saw earlier, that an enzyme efficiency will be found to be involved. Indeed, in some forms of CID in humans, a efficiency of adenosine deaminase has been detected, although foals with CID show no such deficiency. Recent evidence indicates that CID in foals may be associated with a defect of purine metabolism.
There are various other disorders of the immune system that appear to represent blockages at other points in Fig. 3.2. In black Pied Danish cattle, for example, there is an autosomal recessive disease known as lethal trait A-46. It is characterized by thymic hypoplasia (position 2 in Fig. 3.2), which leads to a complete loss of ability to mount a cell-mediated response, while interfering only partially with the production of antibodies. Affected calves usually die by four months of age. A case of complete lack of immunoglobulins but with normal T cell function has been reported in a thoroughbred horse. Known as agammaglobulinaemia, it probably reflects a blockage between the lymphoid precursor cells and the bursal equivalent (position 3 in Fig. 3.2). Selective deficiencies of particular immunoglobins such as IgG2 in Red Danish cattle, and IgM in horses may be due to a specific defect beyond the B cells (position 4 in Fig. 3.2). Defects at other positions have been reported in humans and will probably be found in animals in the future. For a general review of immunodeficiencies in domestic animals, see Perryman (1979).
While most inherited immunodeficiencies are quite rare and are thus not economically important, CID is a serious problem in Arab horses. For example, in 1977 it was reported that 2.3 per cent of 257 foals sampled from 9 states within the USA were affected. And one stud in Australia had the misfortune to import from England two stallions that were both subsequently shown to be carriers of CID. Extensive use of these stallions and their sons and daughters over the years before CID was shown to be an inherited disease, led to the birth of 17 affected foals out of a total of 204, or 8.3 per cent of all foals born in the stud. In Chapter 11 we shall consider alternative programmes that could be used to control CID in such a stud.
Only a small proportion of inherited disorders can be explained currently in biochemical terms. These few are worth studying because the principles that they illustrate must also apply to many other inherited disorders.
If a particular polypeptide acts as an enzyme or is part of an enzyme, them a mutation in the gene that codes for that polypeptide sometimes results in a deficiency of that enzyme, with a consequent blockage in the relevant biochemical pathway at the point where that enzyme is required. Diseases that result from such blockages are called inborn errors of metabolism.
Examples of inborn errors of metabolism occurring in animals include congenital haemolytic anaemia associated with pyruvate kinase deficiency, inborn errors of lysosomal catabolism, porphyria, protoporphyria and dermatosparaxis. In all inborn errors of metabolism, heterozygotes show a level of gene product intermediate between that of the two relevant homozygotes. This provides a relatively easy means of detection of carriers of inherited diseases whose biochemical basis is known.
Two alleles at one locus can exhibit more than one type of gene action.
Genetical heterogeneity of disease occurs when the same clinical signs are associated with more than one genetic disease. If it remains undetected, then such heterogeneity makes it impossible to determine the exact form of inheritance.
In general, recessive diseases are due to enzyme deficiencies while dominant diseases are caused by defects in non-enzymatic polypeptides.
Inherited bleeding disorders, inherited disorders of haemoglobin and inherited immunodeficiencies all provide further illustrations of the principles underlying inherited biochemical diseases.