Patterns of Single-Gene Inheritance II 2024 PDF

Akhobadze Madona M.D., PhD assistant ☺ Patterns of Single-Gene Inheritance II 2024  Content: X-Linked Inheritance, X Inactivation, Dosage Compensation, and the Expression of X-Linked Genes, Pseudoautosomal Inheritance, Mosaicism, Unstable Repeat Expansions, F...

Akhobadze Madona M.D., PhD assistant ☺ Patterns of Single-Gene Inheritance II 2024  Content: X-Linked Inheritance, X Inactivation, Dosage Compensation, and the Expression of X-Linked Genes, Pseudoautosomal Inheritance, Mosaicism, Unstable Repeat Expansions, Fragile X Syndrome, Maternal Inheritance Of Disorders Caused By Mutations In The Mitochondrial Genome Reading: Ch. 7. Thompson & Thompson Genetics in Medicine, Robert L. Nussbaum, Roderick R. McInnes MENDELIAN INHERITANCE The patterns shown by single-gene disorders in pedigrees depend chiey on two factors: whether the phenotype is dominant (expressed when only one chromosome of a pair carries the mutant allele and the other chromosome has a wild-type allele at that locus) or recessive (expressed only when both chromosomes of a pair carry mutant alleles at a locus); the chromosomal location of the gene locus, which may be on an autosome (chromosomes 1 to 22) or on a sex chromosome (chromosomes X and Y) Thus, there are four basic patterns of single-gene inheritance :  -Linked Inheritance Whether an abnormal gene is on an autosome or is X linked has a profound effect on the clinical expression of the disease. First, autosomal disorders, in general, affect males and females equally. For X-linked disorders, the situation is quite different. Males have only a single X and are therefore hemizygous with respect to X-linked genes 46,XY males are never heterozygous for alleles at X linked loci, whereas females can be heterozygous or homozygous at X-linked loci. to compensate for the double complement of X-linked genes in females, alleles for most X-linked genes are expressed from only one of the two X chromosomes in any given cell of a female X-LINKED INHERITANCE Approximately 1100 genes are thought to be located on the X chromosome, of which approximately 40% are presently known to be associated with disease phenotypes. X-LINKED INHERITANCE X Inactivation, Dosage Compensation, and the Expression of X-Linked Genes one X chromosome is largely inactivated in somatic cells in normal females (but not in normal males), thus equalizing the expression of most X-linked genes in the two sexes. The clinical relevance of X inactivation is profound. It leads to females having two cell populations, one in which one of the X chromosomes is active, the other in which the other X chromosome is active  Both cell populations in human females are readily detected for some disorders. For example, in Duchenne muscular dystrophy, female carriers exhibit typical mosaic expression, allowing carriers to be identified by dystrophin immunostaining Depending on the pattern of random X inactivation of the two X chromosomes, two female heterozygotes for an X-linked disease may have very different clinical presentations because they differ in the proportion of cells that have the mutant allele on the active X in a relevant tissue A, A normal female (magnication ×480) B, A male with Duchenne muscular dystrophy (×480) C, A carrier female (×240) Staining creates the bright lines seen here encircling individual muscle bers. Muscle from DMD patients lacks dystrophin staining. Muscle from DMD carriers exhibits both positive and negative patches of dystrophin immunostaining, reecting X inactivation Expression of X-Linked Genes  Recessive and Dominant Inheritance of X-Linked Disorders X-linked “dominant” and “recessive” patterns of inheritance are distinguished on the basis of the phenotype in heterozygous females. Some X-linked phenotypes are consistently expressed in carriers (dominant), whereas others usually are not (recessive) females who are heterozygous for the same mutant allele in the same family may or may not demonstrate the disease, depending on the pattern of random X inactivation and the proportion of the cells in pertinent tissues that have the mutant allele on the active versus inactive chromosome. X-Linked Recessive Inheritance expressed phenotypically in all males who receive it but only in those females who are homozygous for the mutation X-linked recessive disorders are generally restricted to males and rarely seen among females Hemophilia A is a classic X-linked recessive disorder in which the blood fails to clot normally because of a deficiency of factor VIII, a protein in the clotting cascade  Pedigree pattern demonstrating an X-linked recessive disorder such as hemophilia A, transmitted from an affected male through females to an affected grandson and great-grandson Homozygous Affected Females A gene for an X-linked disorder is occasionally present in both a father and a carrier mother, and female offspring can then be homozygous affected, as shown in the pedigree of X-linked color blindness, a relatively common X-linked disorder Most X-linked diseases are so rare, however, that it is unusual for a female to be homozygous unless her parents are consanguineous Consanguinity in an X-linked recessive pedigree for red-green color blindness, resulting in a homozygous affected female  Manifesting Heterozygotes and Unbalanced Inactivation for X-Linked Disease In those rare instances in which a female carrier of a recessive X-linked allele has phenotypic expression of the disease, she is referred to as a manifesting heterozygote. Manifesting heterozygotes have been described for many X-linked recessive disorders, including color blindness, hemophilia A (classic hemophilia, factor VIII deficiency), hemophilia B (Christmas disease, factor IX deficiency), Duchenne muscular dystrophy, Wiskott-Aldrich syndrome (an X-linked immunodeficiency), and several X-linked eye disorders. Characteristics of X-Linked Recessive Inheritance The incidence of the trait is much higher in males than in females. Heterozygous females are usually unaffected, but some may express the condition with variable severity as determined by the pattern of X inactivation. The gene responsible for the condition is transmitted from an affected man through all his daughters. Any of his daughters’ sons has a 50% chance of inheriting it. Characteristics of X-Linked Recessive Inheritance The mutant allele is ordinarily never transmitted directly from father to son, but it is transmitted by an affected male to all his daughters. The mutant allele may be transmitted through a series of carrier females; if so, the affected males in a kindred are related through females. A significant proportion of isolated cases are due to new mutation. X-Linked Dominant Inheritance X-linked phenotype is described as dominant if it is regularly expressed in heterozygotes. X-linked dominant inheritance can readily be distinguished from autosomal dominant inheritance by the lack of male-to-male transmission, which is obviously impossible for X-linked inheritance because males transmit the Y chromosome, not the X, to their sons. X-linked dominant pedigree is that all the daughters and none of the sons of affected males are affected if any daughter is unaffected or any son is affected, the inheritance must be autosomal, not X-linked Pedigree pattern demonstrating X-linked dominant inheritance X-Linked Dominant Inheritance Only a few genetic disorders are classified as X-linked dominant. One example is X-linked hypophosphatemic rickets (also called vitamin D–resistant rickets), in which the ability of the kidney tubules to reabsorb filtered phosphate is impaired.  Characteristics of X-Linked Dominant Inheritance Affected males with normal mates have no affected sons and no normal daughters. Both male and female offspring of female carriers have a 50% risk of inheriting the phenotype. The pedigree pattern is similar to that seen with autosomal dominant inheritance. Affected females are about twice as common as affected males, but affected females typically have milder (although variable) expression of the phenotype.  X-Linked Dominant Disorders with Male Lethality Some of the rare genetic defects expressed exclusively or almost exclusively in females appear to be X-linked dominant conditions that are lethal in males before birth Rett syndrome is a striking disorder that occurs nearly exclusively in females and meets all criteria for being an X-linked dominant disorder that is usually lethal in hemizygous males The syndrome is characterized by normal prenatal and neonatal growth and development, followed by the rapid onset of neurological symptoms and loss of milestones between 6 and 18 months of age. The children become spastic and ataxic, develop autistic features and irritable behavior with outbursts of crying, and demonstrate characteristic purposeless wringing or flapping movements of the hands and arms Rett syndrome Head growth slows and microcephaly develops. Seizures are common (∼50%). Surprisingly, the mental deterioration stops after a few years and the patients can then survive for many decades with a stable but severe neurological disability. Most cases of Rett syndrome are caused by spontaneous mutations in an X-linked gene, MECP2, encoding a DNA-binding protein known as methyl-CpG–binding protein 2. The disease mechanism is unknown but is thought to reflect abnormalities in the regulation of a set of genes in the developing brain. Most female heterozygotes have full-blown Rett syndrome. Males who survive with the syndrome usually have two X chromosomes Pedigree pattern demonstrating an X-linked dominant disorder, lethal in males during the prenatal period.  New Mutation in X-Linked Disorders In males, genes for X-linked disorders are exposed to selection that is complete for some disorders, partial for others, and absent for still others, depending on the fitness of the genotype Patients with hemophilia have only about 70% as many offspring as unaffected males do; that is, the fitness of affected males is about 0.70. Selection against mutant alleles is more dramatic for X-linked disorders such as Duchenne muscular dystrophy (DMD) New Mutation in X-Linked Disorders The disorder is usually apparent by the time the child begins to walk and progresses inexorably, so that the child is confined to a wheelchair by about the age of 10 years and usually does not survive his teens DMD is currently a genetic lethal because affected males usually fail to reproduce. mutant alleles they carry are lost from the population It may, of course, be transmitted by carrier females, who themselves rarely show any clinical manifestation of the disease. Because the incidence of DMD is not changing, mutant alleles lost through failure of the affected males to reproduce are continually replaced by new mutations PSEUDOAUTOSOMAL INHERITANCE Pseudoautosomal inheritance describes the inheritance pattern seen with genes in the pseudoautosomal region of the X and Y chromosome that can exchange regularly between the two sex chromosomes Alleles for genes in the pseudoautosomal region can show male to male transmission, and therefore mimic autosomal inheritance, because they can cross over from the X to the Y during male gametogenesis and be passed on from a father to his male offspring  PSEUDOAUTOSOMAL INHERITANCE Dyschondrosteosis, a dominantly inherited skeletal dysplasia with disproportionate short stature and deformity of the forearm, A greater prevalence of the disease was seen in females as compared with males, suggesting an X-linked dominant disorder, but the presence of male-to-male transmission clearly ruled out strict X-linked inheritance. Mutations in the SHOX gene encoding a homeodomain-containing transcription factor have been found responsible for this condition. SHOX is located in the pseudoautosomal region on Xp and Yp and escapes X inactivation  Pedigree showing inheritance of dyschondrosteosis due to mutations in a pseudoautosomal gene on the X and Y chromosomes The arrow shows a male who inherited the trait on his Y chromosome from his father. His father, however, inherited the trait on his X chromosome from his mother. (From Shears DJ, et al: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis  MOSAICISM Mosaicism is the presence in an individual or a tissue of at least two cell lines that differ genetically but are derived from a single zygote mutations arising in a single cell in either prenatal or postnatal life can give rise to clones of cells genetically different from the original zygote because once the mutation occurs, it could persist in all the clonal descendants of that cell  Mosaicism for mutations in single genes, in either somatic or germline cells, explains a number of unusual clinical observations, such as segmental neurofibromatosis, in which skin manifestations are not uniform and occur in a patchy distribution, and the recurrence of osteogenesis imperfecta, a highly penetrant autosomal dominant disease, in two or more children born to unaffected parents. The population of cells that carry a mutation in a mosaic individual could theoretically be present in some tissues of the body but not in the gametes (pure somatic mosaicism), be restricted to the gamete lineage only and nowhere else (pure germline mosaicism), or be present in both somatic lineages and the germline, depending on when the mutation occurred in embryological development  Schematic presentation of mitotic cell divisions A mutation occurring during cell proliferation, in somatic cells or during gametogenesis, leads to a proportion of cells carrying the mutation—that is, to either somatic or germline mosaicism  Somatic Mosaicism A mutation affecting morphogenesis and occurring during embryonic development might be manifested as a segmental or patchy abnormality, depending on the stage at which the mutation occurred and the lineage of the somatic cell in which it originated NF1 is sometimes segmental, affecting only one part of the body. Segmental NF1 is caused by mosaicism for a mutation that occurred after conception  Germline Mosaicism the chance that an autosomal or X-linked disorder caused by a new mutation could occur more than once in a sibship is low because spontaneous mutations are generally rare well-documented examples where parents who are phenotypically normal and test negative for being carriers have more than one child affected with a highly penetrant autosomal dominant or X-linked disorder. Such unusual pedigrees can be explained by germline mosaicism  IMPRINTING IN PEDIGREES According to Mendel’s laws of heredity, a mutant allele of an autosomal gene is equally likely to be transmitted from a parent, of either sex, to an offspring of either sex; similarly, a female is equally likely to transmit a mutated X-linked gene to a child of either sex Originally, little attention was paid to whether the sex of the parent had any effect on the expression of the genes each parent transmits. However, in some genetic disorders such as Prader-Willi syndrome and Angelman syndrome, the expression of the disease phenotype depends on whether the mutant allele has been inherited from the father or from the mother, a phenomenon known as genomic imprinting  IMPRINTING IN PEDIGREES When a mutation of the imprinting control region is inherited from the mother, both the paternal allele, which is normally silent in kidney tubules, and the maternal allele, which is silenced in these tissues because of the deletion, fail to be expressed Individuals who inherit the mutation from their fathers, however, are asymptomatic heterozygotes because their maternal copy of GNAS, with its imprinting control region intact, is expressed normally in these tissues UNSTABLE REPEAT EXPANSIONS the responsible mutation, once it occurs, is stable from generation to generation; that is, all affected members of a family share the identical inherited mutation In contrast, an entirely new class of genetic disease has been recognized, diseases due to unstable repeat expansions, characterized by an expansion within the affected gene of a segment of DNA consisting of repeating units of three or more nucleotides in tandem repeat unit often consists of three nucleotides, such as CAG or CCG, and the repeat will be CAGCAGCAG... CAG or CCGCCGCCG... CCG. As the gene is passed from generation to generation, however, the number of repeats can increase (undergoes expansion), far beyond the normal polymorphic range, leading to abnormalities in gene expression and function  The degree of expansion of the repeat unit that causes disease is sometimes subtle (as in the rare disorder oculopharyngeal muscular dystrophy) and sometimes explosive (as in congenital myotonic dystrophy or severe fragile X syndrome) These disorders are Huntington disease and other progressive neurodegenerative diseases, such as spinobulbar muscular atrophy and autosomal dominant spinocerebellar ataxias (referred to as polyglutamine disorders because they result from expansions of the triplet CAG encoding glutamine residues); fragile X syndrome; myotonic dystrophy; and Friedreich ataxia.  Huntington Disease well-known disorder that illustrates many of the common genetic features of the polyglutamine disorders caused by expansion of an unstable repeat The neuropathology is dominated by degeneration of the striatum and the cortex. Patients first present clinically in midlife and manifest a characteristic phenotype of motor abnormalities (chorea, dystonia), personality changes, a gradual loss of cognition, and ultimately death. For a long time, HD was thought to be a typical, autosomal dominant condition. The disease is passed from generation to generation with a 50% risk to each offspring, and heterozygous and homozygous patients carrying the mutation have very similar phenotypes, although homozygotes may have a more rapid course of their disease.  Huntington Disease however, obvious peculiarities in its inheritance that could not be explained by simple autosomal dominant inheritance. age at onset of HD is variable; only about half the individuals who carry a mutant HD allele show symptoms by the age of 40 years. the disease appears to develop at an earlier and earlier age when it is transmitted through the pedigree, a phenomenon referred to as anticipation, but only when it is transmitted by an affected father and not by an affected mother.  Approximate age at onset of Huntington disease with the number of CAG repeats found in the HD gene The solid line is the average age at onset, and the shaded area shows the range of age at onset for any given number of repeats = 1/16  Spinobulbar Muscular Atrophy and Other Polyglutamine Disorders In addition to HD, other neurological diseases are caused by CAG expansions encoding polyglutamine, such as X-linked recessive spinobulbar muscular atrophy and the various autosomal dominant spinocerebellar ataxias. These conditions differ in the gene involved, the normal range of the repeat, the threshold for clinical disease caused by expansion, and the regions of the brain affected; they all share with HD the fundamental characteristic that results from instability of a stretch of repeated CAG nucleotides leading to expansion of a glutamine tract in a protein.  Fragile X Syndrome most common heritable form of moderate mental retardation and is second only to Down syndrome among all causes of mental retardation in males cytogenetic marker on the X chromosome at Xq27.3, a “fragile site” in which the chromatin fails to condense properly during mitosis 1 in 4000 male births and is so common that it requires consideration in the differential diagnosis of mental retardation in both males and females a massive expansion of another triplet repeat, CGG, located in the 5′ untranslated region of the fi rst exon of a gene called FMR1 (fragile X mental retardation 1)  Myotonic Dystrophy A third unstable repeat expansion disease is myotonic dystrophy (dystrophia myotonica, or DM), inherited as an autosomal dominant myopathy characterized by myotonia, muscular dystrophy, cataracts, hypogonadism, diabetes, frontal balding, and changes in the electroencephalogram Because congenital DM is due to huge expansions in the many thousands, this form of myotonic dystrophy is therefore almost always inherited from an affected mother.  Friedreich Ataxia (FRDA), a spinocerebellar ataxia, constitutes a fourth category of triplet repeat disease. The disease is inherited in an autosomal recessive pattern, in contrast to HD, DM, and fragile X syndrome. The disorder is usually manifested before adolescence and is generally characterized by incoordination of limb movements, difficulty with speech, diminished or absent tendon refl exes, impairment of position and vibratory senses, cardiomyopathy, scoliosis, and foot deformities. In most cases,  Friedreich Ataxia Friedreich ataxia is caused by amplifi cation of still another triplet repeat, AAG, located this time in an intron of a gene that encodes a mitochondrial protein called frataxin, which is involved in iron metabolism.  The Mitochondrial Genome Mitochondrial genome consists of a circular chromosome, 16.5 kb in size, that is located inside the mitochondrial organelle, not in the nucleus Most cells contain at least 1000 mtDNA molecules, distributed among hundreds of individual mitochondria A remarkable exception is the mature oocyte, which has more than 100,000 copies of mtDNA, composing about one third of the total DNA content of these cells. Mitochondrial DNA (mtDNA) contains 37 genes. The genes encode 13 polypeptides that are subunits of enzymes of oxidative phosphorylation, two types of ribosomal RNA, and 22 transfer RNAs required for translating the transcripts of the mitochondria-encoded polypeptides.  The Mitochondrial Genome The remaining polypeptides of the oxidative phosphorylation complex are encoded by the nuclear genome. More than 100 different rearrangements and 100 different point mutations have been identied in mtDNA that can cause human disease, often involving the central nervous and musculoskeletal systems (e.g., myoclonic epilepsy with ragged-red bers) The diseases that result from these mutations show a distinctive pattern of inheritance because of three unusual features of mitochondria: replicative segregation, homoplasmy and heteroplasmy, and maternal inheritance  Maternal Inheritance of mtDNA Sperm mitochondria are generally eliminated from the embryo, so that mtDNA is inherited from the mother. Thus, all the children of a female who is homoplasmic for a mtDNA mutation will inherit the mutation, whereas none of the offspring of a male carrying the same mutation will inherit the defective DNA. The maternal inheritance of a homoplasmic mtDNA mutation causing Leber hereditary optic neuropathy  Replicative Segregation The rst unique feature of the mitochondrial chromosome is the absence of the tightly controlled segregation seen during mitosis and meiosis of the 46 nuclear chromosomes At cell division, the multiple copies of mtDNA in each of the mitochondria in a cell replicate and sort randomly among newly synthesized mitochondria The mitochondria, in turn, are distributed randomly between the two daughter cells. This process is known as replicative segregation.  Homoplasmy and Heteroplasmy most cells contain many copies of mtDNA molecules One daughter cell may, by chance, receive mitochondria that contain only a pure population of normal mtDNA or a pure population of mutant mtDNA - homoplasmy Alternatively, the daughter cell may receive a mixture of mitochondria, some with and some without mutation - heteroplasmy  Pedigree of Leber hereditary optic neuropathy, a form of spontaneous blindness caused by a defect in mitochondrial DNA Inheritance is only through the maternal lineage, in agreement with the known maternal inheritance of mitochondrial DNA. No affected male transmits the disease.  Characteristics of Mitochondrial Inheritance All children of females homoplasmic for a mutation will inherit the mutation; the children of males carrying a similar mutation will not. Females heteroplasmic for point mutations and duplications will pass them on to all of their children. However, the fraction of mutant mitochondria in the offspring, and therefore the risk and severity of disease, can vary considerably, depending on the fraction of mutant mitochondria in their mother as well as on random chance operating on small numbers of mitochondria per cell at the oocyte bottleneck.  Characteristics of Mitochondrial Inheritance Heteroplasmic deletions are generally not heritable. The fraction of mutant mitochondria in different tissues of an individual heteroplasmic for a mutation can vary tremendously, thereby causing a spectrum of disease among the members of a family in which there is heteroplasmy for a mitochondrial mutation. Pleiotropy and variable expressivity in different affected family members are frequent. გმადლობთ , ყურადღებისთვის !!!