4. Epigenetics
5.4. Autosomal dominant inheritance
Glucose-6-phosphate-68 Genetics and genomics
dehidrogenase deficiency) (see 5.4.4). Either an altered function of the modifier genes or some epigenetic event lies in the background of the inducing effect.
Table 5.2 shows a short summary of the occurrence of the above mentioned terms/phenomena and in connection with some autosomal diseases.
Multiplex allelism Allele heterogeneity Locus heterogeneity Variable expressivity Incomplete penetrance Pleiotropy Influence of paternal age Anticipation Heterozygote advantage Phenocopy
Achondroplasia X X
Marfan Syndrome X X X X
Osteogenesis
imperfecta ? X X X
Familial hypercholes-terolemia
X X
Polydactyly X X X
Huntington Chorea X
Deafness X
Cystic fibrosis X X X X
Phenylketonuria X
Albinism (albino
phenotype) X X
CAH X X X X
Xeroderma
pigmentosum X X
Sickle cell anemia X X
Table 5.2. Summary of the genetic characteristics and phenomena in connection with some AD and AR diseases. In column „Phenocopy” those diseases are shown whose negative (mutated) gene effect can be compensated either by diet or by medicaments. Therefore the
treatment results in fully or partially healthy phenotype.
In certain cases there is no difference in the severeness of the symptoms between homozygotes and heterozygotes. For instance in Huntington Chorea one mutated allele of huntingtin gene already codes for such a deeply malfunctioning protein, - as a negative dominant mutation- that it elicits the lethal outcome. (Not to be mistaken: the onset and the slower or faster development of the disease does not depend on the homozygous or heterozygous genotype, but on the trinucleotide repeat number in the mutated allele. See 5.3.2.: Anticipation.) On the other hand the homozygous state can result significantly more severe outcome of certain diseases than the heterozygous one.
(Examples: Osteogenesis imperfecta, Marfan syndrome, Waardenburg syndrome or Familial hypercholesterolemia.)
Homozygosity is quite rare in AD diseases, since both parents need to be affected.
(When new mutations appear, they practically never occur at the same time on both alleles of an individual.) The disease is sometimes accompanied from so severe symptoms that the disease itself is the obstacle of starting a family. As the disease can be recognized due to the dominant phenotype, sometimes affected parents themselves refuse to have children, they do not risk it, or finally they decide to visit a genetic counselling. As it has been already discussed in Chapter 5.3 new mutations always arise, therefore the „disease gene” cannot be eliminated from a population.
Possible causes of heterozygous dominance are haploinsufficiency, dominant negative effect and loss of function or gain of function mutations.
The AD inherited diseases are caused mostly by the mutations of structural protein genes, regulatory protein genes, receptor genes and proto-oncogenes. Pleiotropy, variable expressivity, incomplete penetrance, arousal of a new mutation and the influence of paternal age are particular characteristics of this kind of inheritance. These will be discussed in the following paragraphs in connection with a few diseases as examples.
5.4.2. Diseases due to the mutation of structural genes
5.4.2.1. Marfan syndrome
Fibrillin gene is mutated. Pleiotropy in this case is clearly understandable, since fibrillin is one of the most important extracellular protein present in the elastic and non-elastic connective tissues. Multiple organs can be affected: lungs, skin, kidneys, skeletal system, vascular system, cornea, etc. The type of the affected organs and the severeness of the symptoms may show individual differences, implicating variable expressivity. The arousal of the mutation shows strong correlation with paternal age.
5.4.2.2. Osteogenesis imperfecta
The different mutations of collagen gene produce differently severe symptoms. The collagen gene family comprises 45 genes, distributed on different chromosomes, coding for proteins of somewhat different nature. Considering that collagen is the most abundant protein in the extracellular matrix, it is not surprising that the mutations of these genes have pleiotropic effect as well. Also expressivity is variable; the fragility of the bones in homozygotes can be so severe, that it causes death already during the process of birth. On the other hand it is possible that either deafness - as a result of the abnormal development of the ear bones, or breakable bones develop only.
Sometimes the inheritance of Osteogenesis imperfecta shows incomplete penetrance. It has not been revealed exactly yet, why some heterozygous persons do not show the symptoms in AD diseases, but it is suggested that modifier genes are involved in the process.
70 Genetics and genomics
5.4.3. Diseases due to mutations of receptor genes
5.4.3.1. Achondroplasia
The disease is caused by the mutation of FGFR3 (fibroblast growth factor receptor type 3). Depending on the locus of the mutation in the gene, three different diseases are distinguished: - Achondroplasia, Hypochondroplasia and Tanatophoroplasia - . We are facing allele heterogeneity here.
The mutation is a „gain of function” mutation; the receptor stays active without ligand as well. The mutation arises usually as new mutation and it shows strong correlation with the age of the father.
5.4.3.2. Familial hypercholesterolemia: it is a relatively frequent disease with a prevalence of 1:500. The severeness of the symptoms depends on whether the genotype is homozygous or heterozygous. More than 100 mutations have been identified in the gene of LDL receptor- this is a case of multiplex allelism.
5.4.3.3. Polycystic kidney disease: with a prevalence of 1:800, it is the most frequent AD disease. The disease is connected to the malfunction of a receptor-ion channel complex that consists of two polycyistin proteins, regulating G-protein signalization and a membrane bound Ca++ channel. PKD1 gene codes for protein Polycystin1 and PKD2 gene for Polycystin2. 80% of the mutations hit the first gene. The onset of the disease is in early or late adulthood, it shows variability even in the same family regarding both the time of the onset and the severeness of the symptoms. The differences depend on environmental factors, as infections can promote the development of the symptoms. As for genetic influence, the manifestation may depend on the site of the mutation in the affected allele. Additionally, the outcome of the disease is strongly influenced by modificator genes whose polymorphism further complicates the picture. Some polymorphisms of nitrogen-monoxide synthase (eNOS) induce an early and more severe development of the disease.
5.4.4. Mutations of the gene of a protein with a yet unknown function
5.4.4.1. Huntington Chorea: it is caused by a trinucleotide repeat expansion mutation.
The role of the huntingtin protein, coded by the healthy allele, has not been revealed yet.
A gain of malfunction appears with the increase of the number of CAG repeats. The increase of the repeat number occurs mostly in the paternal germline (see 5.3 and 5.4.1).
5.4.5. Mutation of Protooncogenes
See 5.6.
5.4.6. Pharmacogenetic diseases
There are some monogenic diseases which - despite their mutated genotype - get manifested only in the presence of particular inducing environmental effects. An older classification ranged pharmacogenetic diseases into the group of ecogenetic diseases.
The term „pharmacogenetic” is not exact either, as the inducing factors can be others than only medicaments.
5.4.6.1. Porfiria
The affected genes code for the enzymes of the steps of haeme and porphyrin synthesis.
Different types of Porfirias are distinguished, depending on the enzyme whose gene had
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.