Genetic diseases and mutations

A child with the Down syndrome, which is a chromosomal disorder. Patients have three (21) chromosomes.

Broadly speaking, genetic diseases can be classified into three categories:

1. diseases related to single genes with large effects, also known as Mendelian diseases, such disorders are caused by mutations in a single but ‘important’ gene. With a very low lifetime frequency, such diseases are characterized by a very high penetrance. Penetrance is a term used to denote the ratio between the individuals that manifest the disease’s symptoms and those who carry the mutation.
2. chromosomal diseases, patients’ cells have an abnormal number of chromosomes.
3. multigenic diseases, caused by a constellation of mutations. Mutations may occur in coding or non-coding sequences and they ‘collaborate’ to the symptomatic development of the disease. In contrast to Mendelian disorders, Multigenic disorders are more frequent and less penetrant. The smaller penetrance is due to the inability of single mutated genes to develop the disease.

Sickle cell anemia is caused by the substitution of glutamic acid, an acidic amino acid, with valine, a neutral amino acid. Being glutamic acid polar and valine non-polar, the substitution results in a deformation of hemoglobin and erythrocytes.

It is evident from the above classification that mutations play an important role in the development of genetic diseases. What is a mutation? A mutation is a permanent change in the genome of an individual which is inherited to the progeny. Mutations can consist of nucleotide substitutions(point mutation), nucleotide insertions and nucleotide deletion(frameshift mutations). Point mutations can occur both within a coding sequence and a non coding sequence. Within coding sequences they can be of two kinds: I)nonsense mutations and II)missense mutations. A nonsense mutation occurs when the nucleotide substitution results in the conversion of a non-stop codon into a stop codon. In missense mutations the nucleotide switch results in the substitution of a non-stop codon with another non-stop codon – at a proteic level it corresponds to the substitution of an aminoacid with another aminoacid. Missense mutations can be either conservative or nonconservative. As we know, aminoacids can be acidic, basic or neutral. In conservative missense mutations an acidic, basic and neutral aminoacid is substituted with another acidic basic and neutral aminoacid respectively. In nonconservative missense mutations, on the other hand, an aminoacid of one kind is substituted with an aminoacid of another kind (e.g.:acidic aminoacid with neutral aminoacid). This is the reason why nonconservative missense mutations cause changes in the physical properties of the proteins they code. In addition, point mutations can also occur in non-coding sequences of the genome. In that case they interfere with promoters’ activity or, when they occur within introns, with post-transcriptional splicing.

This image illustrates how the deletion of G causes a shift in the DNA reading frame.

Mutations consisting of deletion or insertion of nucleotides are known as frameshift mutations because they change the DNA reading frame. A frame shift occurs only if the number of deleted/inserted nucleotides is not a multiple of three. Otherwise there will be no reading frame shift.

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