Medical Genetics - V. M. Zaporozhan 2005

Etiology of Hereditary Diseases
Gene Mutations
Phenotypic effect of gene mutations. Genetic and cellular polymorphism of monogenic disorders

As noted earlier, various alterations in The nucleotide sequence of transcribed DNA regions can manifest themselves in the phenotype in different ways. Some of them have no effect whatsoever on the Structure and function of the corresponding protein (silent Mutations). Others lead to alterations in Cell/13.html">Protein Structure, the cessation of its synthesis, or disruptions in The rate of Protein Synthesis (Scheme 2.2).

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Scheme 2.2. Phenotypic effect of Gene Mutations

According to their phenotypic effect, such mutations can be divided into three classes:

— mutations that lead to the inhibition of METABOLISM/31.html">Transcription or Translation Processes, disruption of the normal STRUCTURE AND Functions of Proteins, and result in a complete loss of function (loss-of-function mutations);

— mutations accompanied by a quantitative change in the protein — such alterations most commonly occur due to mutations in regulatory regions;

— mutations that alter protein properties in such a way that they exert a damaging effect on cell viability (gain-of-function mutations).

Mutations may affect structural, transport, and embryonic proteins, as well as Enzymes. The phenotypic effect of a mutation depends on this. Gene mutations can lead to the death of the Organism (lethal effect), The Development of a monogenic disorder, or remain masked until a certain point (triggered by The Influence of drugs or other xenobiotics).

Various mutations (missense, nonsense, frameshift, etc.) can occur within a gene responsible for a monogenic disorder. Therefore, the degree of alteration in Protein Structure and its functions may vary among different patients. This is one of the causes of the genetic polymorphism of Monogenic Diseases, which, in turn, determines the clinical polymorphism of Monogenic Disorders in the population.

Sometimes, different mutations of the same gene alter the structure and function of the protein to such a vastly different extent that they result in clinically entirely distinct diseases. For instance, various mutations in the androgen receptor gene, located at locus Xq11.2-12, lead to three fundamentally different forms of pathology:

1. Kennedy's spinal and bulbar muscular atrophy (Kennedy's disease) is caused by the expansion of trinucleotide CAG repeats in the first exon of the gene. Normally, the number of triplets ranges from 9 to 36, whereas in affected individuals, it ranges from 38 to 72. This leads to an increase in the length of the polyglutamine tract of the protein. The mutant protein acquires cytotoxic properties and contributes to The formation of pathological intranuclear inclusions. The predominant symptoms of the disease are related to Central Nervous system impairment. Androgen receptor function is moderately reduced.

2. In men with azoospermia and oligozoospermia, a moderate increase in the number of trinucleotide repeats in this same exon has been observed.

3. Testicular feminization syndrome is caused by point mutations in the gene. The leading symptom is impaired androgen receptor function. Clinically, the syndrome manifests as a developmental disorder in embryos with an XY karyotype (a female phenotype is formed despite the male karyotype).

Another example: various mutations in the receptor Tyrosine kinase (RET) gene lead to four different disorders, such as familial medullary thyroid carcinoma, Hirschsprung's disease, multiple endocrine neoplasia type 2A (MEN-2A), and type 2B (MEN-2B).

Different mutations of the same gene that lead to distinct diseases are referred to as allelic series (essentially representing multiple alleles). Currently, more than 100 such diseases are known.