4. Epigenetics
5.5. Autosomal recessive inheritance
been mutated in the cascade. The inheritance pattern is mostly autosomal dominant, rarely recessive. Although the mutated alleles are present in the patients, they do not lead to phenotypic appearance unless certain specific environmental factors induce the manifestation of the disease. These factors are from different origins: drugs, alcohol, steroids (for example contraceptives) stress, starvation, light, etc. The classification of Porfirias in internal medicine and their biochemical background will not be discussed in this chapter. Instead, once more, we intend to draw attention to the fact that genes per se are not „omnipotent” and although the monogenic background is clarified, the inheritance pattern of this disease differs significantly from the classical Mendelian schema.
5.4.6.2. Malignant hyperthermia
The disease can be caused by the mutation of at least six different genes. Mutations of CACNA1S and RYR1 (ryanodine receptor) genes are the most frequent. The product of CACNA1S gene regulates the function of ryanodine receptor. As ryanodine receptor regulates the function of Ca++ ion channels, the mutation of either CACNA1 or RYR1 genes results in the efflux of large amounts of Ca++ ions from the sarcoplasmic reticulum to the cytosol due to the faster opening and slower closing of the ion channels.
The increased Ca++ ion concentration causes increased muscle contraction and increased heat production, resulting in unquenchable high fever and even death. This is indeed a pharmacogenic disease as it is exclusively triggered by drugs, namely by those that are commonly used as general anesthetics.
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product significantly increases in the organism; still, there are no signs of the manifestation of the disease.
The phenomenon of pleiotropy can be easily interpreted in the case of enzymopathies, as the affected enzymes often catalyze steps of cascade reactions. If the enzyme is missing from the beginning of the cascade or from a branching point, more than one metabolic process will be probably damaged.
5.5.2.1. Phenylketonuria (PKU). The disease is caused by the lack of phenylalanine hydroxylase enzyme, toxic phenylpyruvate is produced instead of Tyrosine. The enzyme deficiency causes problems in the cascade of Tyrosine conversion. Although Tyrosine is supplemented in the organism with diet, it remains below the normal needs of Tyrosine, therefore DOPA and melanin synthesis suffers damages. PKU can be treated with phenylalanine free or phenylalanine poor diet. While the manifestation of the toxic product can be avoided, light skin color, blue eyes, light hair color remain as characteristic phenotype in the affected persons. It has been recently discovered that the expression of the several hundred type of phenylalanine hydroxylase mutations is influenced by modificator genes.
5.5.2.2. Classical albinism. The disease is caused by the mutation of tyrosine kinase gene, therefore melanin synthesis fails. This enzyme is a component of a cascade reaction series as well, which explains the pleiotropic effects in albinism. It is to be underlined that the mutations of multiple other genes also result in a similar albino phenotype. The causes of these diseases are deficiencies in intracellular melanin transport. Mutations of several different genes have been identified already, also the diseases have been named differently. (See Table 5.3.)
Table 5.3. Classical albinism and syndromes with albino phenotype.
Their genetic background and the altered / lost cell biological functions.
5.5.2.3. Congenital adrenal hyperplasia (CAH). Pleiotropic effects in congenital adrenal hyperplasia (CAH) can be also explained by failures in the enzymatic cascade of steroid synthesis.
The mutation of cytP450 21-hydroxylase gene causes enzyme deficiency.
http://pediatrics.aappublications.org/content/106/6/1511.full The frequency of CAH among yapi eskimos is 1:300, while in other populations it is about 1:10-15,000. This high prevalence is due to the effect of heterozygote advantage developed against Haemophilus influenzae B.
5.5.2.4. Xeroderma pigmentosum. In Xeroderma pigmentosum one (or more) of the genes of the nucleotide excision repair (NER) of DNA is mutated, this is an example for locus heterogeneity. (See 5.2.). http://ghr.nlm.nih.gov/condition/xeroderma-pigmentosum
5.5.3. Cystic fibrosis
The gene of the disease, the CFTR gene does not belong to any of the gene groups showing „classical” AR inheritance, as the disease is not caused by enzymatic or haemoglobin mutations. The mutation hits the gene of a chloride ion channel regulatory protein. It is the most frequent AR disease in the European populations. There is no evidence of increased mutation rate in this disease; instead heterozygotes might have had increased fitness against cholera over both homozygous genotypes in the middle age. The phenomenon is the so-called heterozygote advantage. (See 5.3. and Chapter 11.) Logically, the phenomenon of pleiotropy in the case of Cystic fibrosis is not a consequence of metabolic cascade discrepancy. It is the consequence of the increased dense mucus secretion in several organs, whose ducts become plugged this way. As pathogens can easily invade the mucus, chronic inflammation develops and the pancreas, the lungs, the seminiferous tubules get into severe conditions. The disease cannot be cured presently, but its severeness can significantly differ among the patients, suggesting the effect of the modificator genes and demonstrating that specific mutations in the same gene can lead to differently damaged protein functions. Out of the more than 800 different mutations that have been identified in the CFTR gene so far, deltaF508 is the most frequent one. This is the deletion of a triplet from exon 10, coding for the 508th aminoacid. Due to the large number of mutations, complex heterozygousy can be assigned to the genotype of the disease (see 5.3).
5.5.4. Haemoglobinopathies
5.5.4.1. Sickle cell anemia. The cause of sickle cell anemia is one of the most well-known mutations. The 6th aminoacid Glutamine is substituted onto Valin in the betaglobin chain of the haemoglobin molecule, due to a transversion substitution in the gene. The mutated haemoglobin is called haemoglobin S. It causes the sickle shape of the red blood cells and gives rise to multiple additional pleiotropic effects. The development of the heterozygote advantage against malaria can also be attributed to this mutation. (See Chapter 11.)
5.5.4.2. Thalassemia. The disease can be caused by several types of mutation. Deletions, frameshift and splicing mutations can arise in both alpha and beta chains of the haemoglobin. This explains at the same time the differences in the severeness and the geographical spreading of the types of Thalassemias. Heterozygotes are protected against malaria in the case of this disease as well.
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