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Chapter 4. Genetic diseases

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.

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