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11.1 Single gene defect or mutation
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If the changes in a genome are restricted to a single gene, a single- gene defect ensues. Usually this involves a point mutation and leads to an altered amino acid sequence in the proteins that are coded in this section of the DNA. A human being has ca. 40-60,000 genes that directly influence characteristics such as hair, skin and eye coloration as well as the development and growth of our bodies. In addition, regulatory regions and the intron sequences also play important roles in turning genes on and off as well as in their correct transcriptions and translations.
Normally, every child obtains half of its genetic material from each parent. The inheritance of monogenetic diseases occurs in accordance with Mendel's laws. In this, one distinguishes among dominant, codominant and recessive genes (Reminder: definitions). Today, such single-gene defects can be diagnosed using DNA analyses.
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Point mutations are small alterations in the genetic material. It affects only one or a few neighboring nucleotides of the DNA sequence. (Details)
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Diseases exist, though, that are not inherited in accordance with Mendel's laws. To these belong defects of the mitochondrial genome as well as illnesses that are due to alterations of various genes (polygeny) or in which environmental factors are involved. (see genome: more complex than the sum of its genes).
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The term genomic imprinting means that the phenotype depends on whether a gene has gone through the paternal or maternal germ line. (Details)
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Autosomal dominant inheritance
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| The disorder already appears when only one of the two genes of a chromosome pair is defective. The risk of a mutation carrier transferring his disease to his offspring amounts to 50%. Examples of such diseases are:
- Aniridia
- Marfan's syndrome
- von Recklinghausen's disease (neurofibromatosis)
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Fig. 2 - Example of an autosomal dominant inheritance of a disease |
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Fig. 2
Example for an autosomal dominant inherited disease. Each carrier of the gene is sick, because the healthy allele is not or not sufficiently expressed.
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Autosomal recessive inheritance
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If the inheritance is recessive the corresponding genes on both chromosomes must exhibit the defect.
Examples for such diseases are:
- Familiar hemochromatosis (the most frequent autosomal recessively inherited disease)
- Cystic fibrosis
- Sickle cell anemia
- Tay-Sachs disease (infantile gangliosidosis)
- Various mucopolysaccharidoses (MPS)
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Fig. 3 - Example of a recessive inheritance of a disease |
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Fig. 3
Cystic fibrosis is an example of an autosomal recessively inherited disease. The risk of a heterozygous parent having a child with the disease amounts to 25%.
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X chromosomal inheritance
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Between 200-300 X chromosome-linked diseases are known. With X chromosomal recessively inherited diseases the affected gene is transferred by phenotypically healthy female carriers. X-chromosomal-dominant inherited diseases are usually lethal.
Examples for X chromosome-linked recessive diseases are:
- Duchenne's muscular dystrophy
- Hemophilia A and B
- Red-green blindness
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Fig. 4 - Example of a recessive X linked inheritance of a disease |
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Fig. 4
Hemophilias A and B are examples for X chromosomal-
recessive inherited diseases. All male descendents are ill (s).
Among the female descendents there are healthy and carriers (c).
Both are phenotypically healthy.
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In a family with red-green blindness and hemophilia, based on their family tree, it was seen for the first time that genes, although they lie near each other and normally are transmitted together (= linkage ), can just as well be inherited separately by descendents. This phenomenon is termed a linkage break. Here the linked genes are torn apart during the "crossing over" process and can be transmitted separately to the offspring.
More details about a family tree with coupling breaks
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In some inherited diseases (triple repeat inheritance) trinucleotide repetitions in the corresponding genes or in the upstream region of the gene have been observed.
Responsible for this are trinucleotides that have expanded themselves at fragile locations over several generations. As soon as a critical size is exceeded (> 200) the gene can no longer encode a normal protein. In these diseases there is a correlation between repeat numbers and inception as well as the severity of the disease.
The fragile X syndrome is such an X chromosomal linked disease.It is responsible for the most frequent form of inherited mental retardation and appears to deviate from the simple X chromosomal linked inheritance mentioned above (1). Concerning its engendering, see: Development of the deviating chromosome structure (duplication).
In the fragile X syndrome the FMRP protein that is encoded by the FMR1 gene is missing. FMRP is present in many types of cells and it also occurs in the cytoplasm of neurons, particularly in their dendrites. FMRP appears to guide the export, cytoplasmic transport and the translation of mRNA, i.e., all the important steps in protein synthesis. It is supposed that FMRP influences dendrite maturation, because in patients with the fragile X syndrome abnormal dendrites are observed, which could also explain the neurological manifestations (mental retardation).
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