Hereditary diseases comprise a large group of illnesses that are passed down from generation to generation; they are those that "run in families." genetic origin, In other words, the cause of these diseases is genetic inheritance. Therefore, to understand what this group of diseases consists of, it is necessary to understand how genetic inheritance works.
It is important to note that Not all genetic diseases are hereditary., Since a genetic mutation that leads to a disease can occur spontaneously or be amplified by environmental factors, we can classify genetic inheritance into two types: Mendelian inheritance and polygenic inheritance, depending on whether it results from a single gene or several. Both types of inheritance are associated with the nuclear genome, but beyond this we find mitochondrial inheritance, which, as its name indicates, is linked to the mitochondria.
Types of genetic inheritance
Mendelian inheritance
Mendelian inheritance is that which is explained as a consequence of a single gene. It is named after the Austrian monk Gregor Mendel, who defined the patterns of this type of inheritance in the 19th century thanks to thousands of experiments carried out with pea plants [1]. Within Mendelian inheritance, a second classification can be made according to the chromosomal location of the gene involved; in this way, we distinguish between autosomal inheritance and sex-linked inheritance.
Autosomal inheritance
The autosomal inheritance Autosomal inheritance is linked to one of the 22 autosomal chromosomes. Since the inheritance of these chromosomes is independent of sex, this type of genetic inheritance affects men and women equally. Autosomal inheritance can be classified as autosomal recessive and dominant. autosomal recessive inheritance It is one in which, for the disease to occur, the person must present two copies of the mutated gene, People with only one copy of the gene are called carriers and do not exhibit any symptoms of the disease [2]. An example of a disease is the cystic fibrosis.
Cystic fibrosis causes severe damage primarily to the lungs and digestive system, although it can affect other organs in the body. At the cellular level, it affects the cells that produce mucus, sweat, and digestive juices—that is, the cells that secrete internal fluids. These fluids, due to cystic fibrosis, become sticky and thick, obstructing internal tubes and ducts, especially in the lungs and pancreas [3].
The gene involved in this hereditary disease is the cystic fibrosis transmembrane conductance regulator gene (CFTR, CFTR (for which it is an acronym in English), which encodes a protein of the same name. The CFTR protein is found in cell membranes and has a key function in controlling the secretion of sodium, chloride, water, and bicarbonate. Alterations in this protein result in thick, sticky mucus in the respiratory, digestive, and reproductive systems, as well as increased salt in sweat [4].
For a person to have cystic fibrosis, since the inheritance pattern is autosomal recessive, they must have two copies of the mutated gene, meaning their parents must each have at least one copy of the mutated gene. However, the parents do not necessarily have to have the disease, as they can both be carriers.
Dominant regional heritage?
The autosomal dominant inheritance It is characterized by the presence A single copy of the mutated gene is enough for the disease to develop..There are many diseases that are inherited in this way, including some types of osteogenesis imperfecta. For example, osteogenesis imperfecta type 3, also known as severe osteogenesis imperfecta, which is a rare disease, that is, it affects less than 5 out of every 10,000 people.
It is characterized by increased bone fragility, leading to frequent fractures, and by deformation of the long tubular bones. Other possible symptoms include short stature, loose ligaments, and osteopenia (decreased bone mineral density). Osteogenesis imperfecta results from a congenital defect in collagen production, which in the case of type 3 is caused by a mutation in the gene that codes for collagen proteins. COL1A1 or COL1A2 [5].
Sex-linked inheritance
The sex-linked inheritance It is transmitted through the sex chromosomes, X or Y. Biological females have two copies of the X chromosome and none of the Y chromosome, while biological males have one copy of the X chromosome and one copy of the Y chromosome. Within sex-linked inheritance, a distinction is made between X-linked inheritance and Y-linked inheritance. Y-linked hereditary diseases, Since biological males are the only ones who have a copy of this chromosome, this type of inheritance is exclusive to men, who will present the disease whenever the mutated gene is present.
In the X-linked diseases, Since women have two copies of this chromosome and men only one, inheritance patterns differ according to sex. Typically, The affected individuals are male., since a single copy of the mutated gene is enough to cause the disease. In the women It is necessary for both copies of the gene to be mutated to suffer from the disease, which is less likely.
The presence of one mutated copy of the gene and a second non-mutated copy can cause milder symptoms, or even no symptoms. In this last case, we are talking about women. carriers.An example of a pathology linked to the X chromosome is... X-linked centronuclear myopathy, Myotubular myopathy, also known as myocardial infarction, is a rare disease that affects skeletal muscle, causing muscle weakness. It is caused by a mutation in the MTM1 gene, It is located on the human X chromosome and affects almost exclusively biological males. Female carriers are generally asymptomatic, although in rare cases women with the disease in heterozygosity have been described [6].
Polygenic inheritance
Polygenic inheritance is a pattern of inheritance determined by genetic factors, which usually affect several genes, and by environmental factors. For this reason, it is also called multifactorial. In diseases that follow this type of inheritance, inheriting one or more pathogenic mutations does not necessarily imply the development of the disease, since environmental factors play a very important role, although it does increase the risk. In these diseases, the risk is calculated... genetic susceptibility or predisposition to suffer from them through mathematical models in which pathogenic polymorphisms are considered to have an additive character. Among the best-known diseases that follow this type of inheritance are diabetes, certain cardiovascular diseases, multiple sclerosis, and some types of cancer.
Breast cancer
One of the most studied examples of hereditary diseases is breast cancer and its relationship with mutations in genes BRCA1 y BRCA2.Although the etiology of breast cancer is not fully understood, hormonal, reproductive, and hereditary risk factors have been described. Regarding the hereditary basis, a subgroup of this type of cancer has been defined, characterized by mutations in BRCA1 and BRCA2. According to the latest epidemiological studies, between 5% and 10% of breast cancers correspond to inherited mutations in these genes.
These genes are classified as tumor suppressor genes because they encode proteins involved in DNA repair. Therefore, mutations in these genes that lead to a loss of function increase the likelihood of developing a tumor [7]. Beyond genetics, other risk factors for breast cancer include age, hormone replacement therapy, such as certain oral contraceptives, and alcohol consumption, among others.
Multiple sclerosis
Another example of hereditary diseases with a polygenic inheritance pattern is the multiple sclerosis. The risk of developing multiple sclerosis in the general population is 0.1–0.21, while for a direct relative of a patient with the disease it is 2.5–51 [8]. Although in a large number of diagnosed cases there is no family history, there are Genetic factors that increase the predisposition to suffer from this disease.
These genetic factors may or may not be inherited. Furthermore, since it is a multifactorial disease, external factors also play a significant role in its development. Multiple sclerosis is a an autoimmune hereditary disease that affects the central nervous systemThe immune system mistakenly attacks the protective sheath (myelin) that covers the neurons, causing communication problems between the brain and the rest of the body.
Most multiple sclerosis diagnoses occur in people between 20 and 40 years of age. For example, in the case of identical twins who share their entire genetic makeup, the risk of one of them developing multiple sclerosis, if the other has it, is 18.21%. In the case of fraternal twins, it is 4.61, while among non-twin siblings, the probability decreases to 2.71.
It is believed that fraternal twins have a higher probability of developing the same conditions than identical twins because they experience the same environmental factors very closely. Currently, More than 200 mutations have been linked to the risk of developing multiple sclerosis. Among the affected genes are, for example, genes that code for various interleukins (immune system proteins), such as IL12A, IL12B, and genes that code for interleukin receptors, such as the gene IL7R [9].
Mitochondrial inheritance
Mitochondrial inheritance encompasses the inheritance of genes included in the mitochondrial genome. Mitochondria are inherited solely through via maternal route, Therefore, this type of inheritance is exclusive to this pathway. Thus, if a woman carries a mutation in her mitochondrial DNA, she will always transmit it to her offspring (both sons and daughters), while men never will. To better understand this type of inheritance, it is necessary to clarify what a mitochondrion is. Mitochondria are cell organelles found in the cytoplasm of cells (that is, outside the nucleus). The main function of the mitochondrion is energy production, and it encodes its own proteins since it contains its own DNA.
The number of mitochondria per cell varies depending on the cell type, and can reach up to 500 mitochondria per cell. This can result in mitochondria within a cell having different genetic material (due to sporadic mutations). This is called heteroplasmy, and determines the severity of diseases caused by this type of inheritance [10]. An example of a disease that exhibits mitochondrial inheritance is Leigh syndrome associated with mitochondrial DNA, a subtype of Leigh syndrome clinically characterized by encephalopathy, lactic acidosis, seizures, cardiomyopathy, respiratory disorders and developmental delay, with onset in infancy or early childhood [11].
Literature
[1] Mendelian inheritance. https://www.genome.gov/es/genetics-glossary/Herencia-mendeliana Accessed: 2022-12-09
[2] Definition of autosomal recessive inheritance – NCI Cancer Dictionary – NCI https://www.cancer.gov/espanol/publicaciones/diccionarios/diccionario-cancer/def/herencia-autosomica-recesiva Accessed: 2022-12-09
[3] Cystic fibrosis – Symptoms and causes – Mayo Clinic https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700 Accessed: 2022-12-09
[4] CFTR function: beyond cystic fibrosis. Xavier Molero Richard. Gastroenterology and Hepatology Continued, 6, 5, 9 2007. doi: 10.1016/S1578-1550(07)75685-1
[5] Rare diseases: osteogenesis imperfecta, a literature review.https://revistasanitariadeinvestigacion.com/enfermedades-raras-osteogenesis-imperfecta-una-revision-bibliografica/ Accessed: 2022-12-09
[6] X-Linked Myotubular Myopathy. James J Dowling, Michael W Lawlor et al. GeneReviews®, August 2018
[7] Hereditary breast and ovarian cancer: primary and secondary prevention in women carrying mutations in the BRCA1 and BRCA2 genes. Gemma Llort, Mercè Peris et al. Clinical Medicine, 128, 12, 3 2007
[8] EMultiple Sclerosis and Genetics – Dr. Mar Mendibe [Published Feb. 2007; revised June 2011; accessed Nov. 2022] Available at: https://www.esclerosismultipleeuskadi.org/esclerosis-multiple-y-genetica/#:~:text=Mar%20Mendibe-,La%20Esclerosis%20M%C3%BAltiple%20(EM)%20NO%20es%20una%20enfermedad%20hereditaria%20aunque,factores%20ambientales%2C%20gen%C3%A9ticos%20e%20inmunol%C3%B3gicos.
[9] The influence of genetics on multiple sclerosis – Multiple Sclerosis Spain. Source: International Federation of Multiple Sclerosis [Published Nov. 2018; Accessed Nov. 2022] Available at: https://esclerosismultiple.com/genetica-en-esclerosis-multiple/
[10] Mitochondrial Inheritance – Michigan Genetics Resource Center https://migrc.org/teaching-tools/genetic-inheritance-patterns/mitochondrial/ Accessed: 2022-12-09[11] Orphanet: Leigh syndrome associated with mitochondrial DNA https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=ES&Expert=255210 Accessed: 2022-12-09
