Medical Genetics - V. M. Zaporozhan 2005

Monogenic Disorders
Etiology of Monogenic Disorders

Monogenic Disorders are conditions caused by a mutation in a single Gene. A common feature among them is inheritance according to Mendelian laws. Currently, over 4,000 monogenic Hereditary diseases are known, and the total number of Mendelian traits in humans exceeds 16,000 (OMIM, 2005).

Monogenic Diseases are caused by Gene Mutations. Mutations that lead to hereditary diseases are termed pathological. Humans possess approximately 30,000 genes, yet the number of monogenic hereditary diseases is significantly smaller. This is because alterations in the Introduction/19.html">Primary Structure of more than 50% of Proteins result in the death of Cells or early embryos. Such proteins are called monomorphic, as they maintain essential cellular Functions.

Mutations in other genes are compatible with life but result in monogenic disorders. These alterations may affect structural, transport, or embryonic proteins, Enzymes, METABOLISM/31.html">Transcription factors, regulatory proteins, and others. The Phenotypic effect of a mutation and the clinical manifestations of a monogenic disease depend on which protein's synthesis is altered and in what manner. Mutations in certain genes are lethal to Gametes or embryos. The lethal effect of such gene mutations is frequently observed prior to implantation—conception does not occur in fertile women despite normal sexual activity. Lethal genes may be the cause of spontaneous abortions or stillbirths, though the quantitative contribution of gene mutations to antenatal and perinatal mortality remains insufficiently studied today. If The Development of an embryo carrying a pathological gene mutation is not halted at early stages, the pathological gene may manifest in the following ways:

— through Congenital Malformations (primarily involving genes responsible for embryonic development and transcription factors);

— through Metabolic Disorders (genes encoding enzymes, receptors, transport proteins, etc.);

— through mixed effects.

Mutations can be dominant or recessive (dominance and recessiveness refer to the sufficiency or insufficiency of the remaining normal allele to ensure normal function).

As a rule, disorders associated with mutations in enzyme-encoding genes are recessive. These mutations reduce enzymatic activity. In heterozygotes, the normal allele provides 50% of enzymatic activity, which is sufficient for normal organismal function (haplosufficient mutation). Therefore, individuals carrying a single mutant gene allele remain healthy, although they exhibit reduced enzymatic activity detectable by biochemical assays. In this case, the normal gene allele is considered dominant, and the mutant allele is recessive.

However, there are always exceptions to the general rule. Diseases caused by impaired functions of non-enzymatic Proteins can also be recessive. For instance, cystic fibrosis is caused by a functional defect in the chloride channel protein. In β-thalassemia, the synthesis of β-globin chains and the assembly of adult Hemoglobin are impaired.

Dominant mutations more frequently affect structural genes that encode Polypeptides of proteins with a quaternary structure. The normal gene ensures 50% production of the normal polypeptide. However, when The quaternary structure is formed, both normal and mutant polypeptides are incorporated into the protein, ultimately disrupting its function. Consequently, the normal allele cannot secure a normal phenotype (haploinsufficient type). For example, most disorders associated with mutations in Collagen genes are inherited as dominant traits.

In populations, dominant mutations become apparent immediately, whereas recessive ones can persist in a heterozygous state for extended periods and manifest only in the offspring of two heterozygous parents.

Mutations can affect autosomal and sex-chromosomal genes. They may also be germline (arising in Germ Cells) or somatic. Germline mutations lead to the full form of a monogenic disease, in which every Cell of the Organism carries the mutant allele. Somatic mutations result in a mosaic form of a hereditary disorder. Somatic mosaicism has been described in more than thirty monogenic diseases.