Etiology Genetic diseases are a group of diseases of heterogeneous clinical presentation, which are caused by gene mutations. The reason for combining them into a single group is the etiological genetic features and, respectively, their patterns of inheritance in families and communities. Since single-gene mutations are the etiological factor of genetic diseases, then the patterns of their inheritance correspond to Mendel laws of segregation, i.e. formal genetics of genetic hereditary diseases do not differ in any way from the “behavior” of any Mendelian trait in a family. The “behavior” of some pathological genes may deviate from Mendel and Morgan laws due to phenotypic effects (lethality, sterility). However, it is necessary to immediately clarify the content of the concepts of human “gene mutations” and “Mendelian heredity”.
Firstly, numerous studies of different hereditary diseases and the entire human genome allow discussing the variety of single-gene mutation types responsible for hereditary diseases. All types of human genetic mutations leading to hereditary diseases have been described: missense, nonsense, frameshift, deletions, insertions, splicing disorders, and trinucleotide repeat expansions (increasing copy numbers of the trinucleotide repeats). Any of these types of mutations are potential causes of hereditary diseases. Moreover, different mutations in a single-gene can result in the same disease. For example, there are about 300 disease-causing mutations (more than 1500 in total) in the cystic fibrosis gene, which can be subdivided into the following types: deletions, missense, nonsense, frameshift, splicing disorders. More than 30 pathological mutations were identified in the phenylketonuria gene (missense, nonsense, deletions, splicing disorders).
Secondly, in certain cases, modern genetics, fully accepting Mendelism, introduces its improvements. These are the conventionality of the concepts of dominance and recessiveness, parent-specific expression of either the maternal or the paternal allele (imprinting), complex gene interactions, gonadal mosaicism, etc. Moreover, scientists discovered that mutations in different parts of the same gene may lead to different diseases. For example, mutations in different parts of the RET oncogene are responsible for four clinically different hereditary diseases: two types of polyendocrine adenomatosis (ZA and ZB), familial medullary thyroid carcinoma, and familial Hirschsprung disease.
Mutations responsible for hereditary diseases may affect structural, transport and embryonic proteins and enzymes.
Classes of proteins associated with monogenic diseases may be found in all cellular constituents (Table 4.1).
Table 4.1. Examples of classes of proteins associated with monogenic diseases
| Parts of cells, functions | Produced protein | Examples of diseases |
| Nucleus | | |
| Developmental transcriptional factor | PАХ 6 | Aniridia |
| Genomic integration | BRCA1, BRCA2 | Mammary cancer |
| DNA mismatch repair proteins | Hereditary non-polyposis colon cancer |
| RNA translation regulation | FMRP (inhibits translation by binding RNA) | Fragile X syndrome |
| Chromatin-associated proteins | MeCP2 (transcriptional repression) | Rett syndrome |
| Tumor suppressors | Rb protein | Retinoblastoma |
| Oncogenes | BCR-ABL oncogene | Chronic myeloid leukemia |
| Cytoplasm | | |
| Metabolic enzymes | Phenylalanine hydroxylase | Phenylketonuria |
| ADA | Severe combined immunodeficiency |
| Cytoskeleton | Dystrophin | Duchenne muscular dystrophy |
| Organelles | | |
| Mitochondria | | |
| Oxidative phosphorylation | ND1-protein of the electron transport chain | Leber hereditary optic neuropathy |
| Translation of mitochondrial proteins | tRNALeu | Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes |
| 12S RNA | Sensorineural deafness |
| Lysosomes | | |
| Lysosomal enzymes | Hexosaminidase A | Tay–Sachs disease |
| Alpha-L-iduronidase deficiency | Hurler syndrome |
| Cell membrane | | |
| Hormone receptors | Androgen receptor | Androgen insensitivity |
| Growth factor receptors | FGFR3-receptor | Achondroplasia |
| Metabolic receptors | LDL-receptor | Hypercholesterolemia |
| Ion transport | CFTR | Cystic fibrosis |
| Antigen presentation | HLA locus DQ β 1 | Type 1 diabetes mellitus |
| Extracellular proteins | | |
| Transport | β-Adrenoglobin | Sickle cell anemia |
| β-Thalassemia |
| Morphogenesis | Sonic hedgehog | Holoprosencephaly |
| Inhibition of proteases | α1-Antitrypsin | Emphysema, liver diseases |
| Hemostasis | Factor VIII | Hemophilia A |
| Hormones | Insulin | Rare forms of type 2 diabetes |
| Extracellular matrix | Type I collagen | Osteogenesis imperfecta |
| Inflammation, response to infection | Complement factor H | Age-related macular degeneration |
Note. CFTR — cystic fibrous transmembrane regulator; HLA — human leukocyte antigen; RNA — ribonucleic acid.
Regulation of protein synthesis occurs at different levels: pretranscriptional, transcriptional and translational. It can be assumed that hereditary abnormalities may appear at any of these levels determined by corresponding enzymatic reactions. If we assume that the human genome consists of approximately 30,000 genes, each gene can mutate and the control synthesis of a structurally different protein, moreover, many genes are known to exhibit alternative splicing, then hereditary diseases should be of relatively equal number. Furthermore, according to modern data, up to several hundred variants of mutations (different types in different parts of the gene) may occur in each gene. As a matter of fact, changes in the genetic nature (primary structure) of more than 50% of proteins would lead to cell death, consequently the mutations will not cause hereditary diseases. These are so-called monomorphic proteins. These proteins are responsible for basic cell functions, conservatively maintaining the stability of the organization of this cell at the species level.