Pathology (genetic diseases 4)
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What are Some general principles that apply to trinucleotide repeats diseases?
- The causative mutations are associated with the expansion of a stretch of trinucleotides that usually share the nucleotides G and C. In all cases the DNA is unstable, and an expansion of the repeats above a certain threshold impairs gene function in various ways.
- The proclivity to expand depends strongly on the sex of the transmitting parent. In the fragile-X syndrome, expansions occur during oogenesis, whereas in Huntington disease they occur during spermatogenesis.
- From a mechanistic standpoint, the mutations can be divided into two groups. In the first group of disorders, exemplified by fragile-X syndrome and myotonic dystrophy, the repeat expansions occur in noncoding regions, whereas in other disorders, such as Huntington disease, expansions occur in the coding regions
In the fragile-X syndrome, expansions occur during................ , whereas in Huntington disease they occur during ...................
What are the expansion affecting noncoding region?
- Fragile-X syndrome: FMRI (FRAXA), Xq, FMR-1 protein (FMRP), CGG
- Friedreich ataxia: FXN, 9q, Frataxin, GAA
- Myotonic dystrophy: DMPK, 19q, Myotonic dystrophy protein kinase (DMPK), CTG
What are the expansion affecting coding region?
- Huntington disease--> HTT, 4p, CAG
- SCA--> CAG
True or False: The pathogenetic mechanisms underlying disorders caused by mutations that affect coding regions is distinct from those in which the expansions affect noncoding regions
What are the features of expansion in coding region?
- Usually involve CAG repeats coding for polyglutamine tracts in the corresponding proteins.
- Such “polyglutamine diseases” are characterized by progressive neurodegeneration, typically striking in midlife. Polyglutamine expansions lead to toxic gain of function, whereby the abnormal protein interferes with the function of the normal protein.
- In most cases the proteins are misfolded and tend to aggregate; the aggregates may suppress transcription of other genes, cause mitochondrial dysfunction, or trigger the unfolded-protein stress response and apoptosis.
- A morphologic hallmark of these diseases is the accumulation of aggregated mutant proteins in large intranuclear inclusions.
What is the morphological hallmark of polyglutamine disease?
Accumulation of aggregated mutant proteins in large intranuclear inclusions.
What are the features of expansion diseases in noncoding region?
- The resulting mutations are loss-of-function type, since protein synthesis (e.g., FMRP) is suppressed.
- Typically, such disorders affect many systems.
- Finally, many noncoding repeat disorders are characterized by intermediate-size expansions, or premutations, that expand to full mutations in germ cells.
What are the two mcc genetic of MR?
What is the genetic of fragile X syndrome?
- It is an X-linked disorder characterized by an inducible cytogenetic abnormality in the X chromosome and an unusual mutation within the familial mental retardation-1 (FMR1) gene.
- The cytogenetic alteration is seen as a discontinuity of staining or as a constriction in the long arm of the X chromosome when cells are cultured in a folate-deficient medium. Because it appears that the chromosome is “broken” at this locale, it is referred to as a fragile site
What are the clinical features of Fragile X syndrome in male?
- In fragile-X syndrome, the affected males are mentally retarded, with an IQ in the range of 20 to 60.
- They express a characteristic physical phenotype that includes a long face with a large mandible, large everted ears, and large testicles (macro-orchidism).
- Hyperextensible joints, a high arched palate, and mitral valve prolapse noted in some patients mimic a connective tissue disorder.
- The most distinctive feature is macro-orchidism, which is observed in at least 90% of postpubertal males
What is the most distinctive features of fragile X syndrome?
macro-orchidism, which is observed in at least 90% of postpubertal males
What are the unusual patterns seen in pedigree of fragile X syndrome?
- Carrier males: Approximately 20% of males who, by pedigree analysis and by molecular tests, are known to carry a fragile-X mutation are clinically and cytogenetically normal. Because carrier males transmit the trait through all their daughters (phenotypically normal) to affected grandchildren, they are called normal transmitting males.
- Affected females: 30% to 50% of carrier females are affected (i.e., mentally retarded), a number much higher than that in other X-linked recessive disorders.
- Risk of phenotypic effects: Risk depends on the position of the individual in the pedigree. For example, brothers of transmitting males are at a 9% risk of having mental retardation, whereas grandsons of transmitting males incur a 40% risk.
- Anticipation: This refers to the observation that clinical features of fragile-X syndrome worsen with each successive generation, as if the mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons and great-grandsons
What are the changes in FMR1 gene that result in Fragile X syndrome?
- FMR1 gene is characterized by multiple tandem repeats of the nucleotide sequence CGG in its 5′ untranslated region.
- In the normal population, the number of CGG repeats is small, ranging from 6 to 55 (average, 29).
- The presence of clinical symptoms and a cytogenetically detectable fragile site is related to the amplification of the CGG repeats.
- Thus, normal transmitting males and carrier females carry 55 to 200 CGG repeats. Expansions of this size are called premutations.
- In contrast, affected individuals have an extremely large expansion of the repeat region (200–4000 repeats, or full mutations). Full mutations are believed to arise by further amplification of the CGG repeats seen in premutations
How does repeat expansion occur in fragile X syndrome?
- Carrier males transmit the repeats to their progeny with small changes in repeat number.
- When the premutation is passed on by a carrier female, however, there is a high probability of a dramatic amplification of the CGG repeats, leading to mental retardation in most male offspring and 50% of female offspring.
- Thus, it seems that during the process of oogenesis, but not spermatogenesis, premutations can be converted to mutations by triplet-repeat amplification.
- This explains the unusual inheritance pattern; that is, the likelihood of mental retardation is much higher in grandsons than in brothers of transmitting males because grandsons incur the risk of inheriting a premutation from their grandfather that is amplified to a “full mutation” in their mothers' ova.
- By comparison, brothers of transmitting males, being “higher up” in the pedigree, are less likely to have a full mutation
Why is the likelihood of mental retardation in fragile X syndrome is much higher in grandsons than in brothers of transmitting males ?
because grandsons incur the risk of inheriting a premutation from their grandfather that is amplified to a “full mutation” in their mothers' ova
Why are only 50% of the females with the full mutation in fragile X clinically affected?
Presumably in those that are clinically affected there is unfavorable lyonization (i.e., there is a higher frequency of cells in which the X chromosome carrying the mutation is active).
What are the clinical significance of premutation in Fragile X syndrome?
Approximately 30% of females carrying the premutation have premature ovarian failure (before the age of 40 years), and about one third of premutation-carrying males exhibit a progressive neurodegenerative syndrome starting in their sixth decade. This syndrome, referred to as fragile X–associated tremor/ataxia, is characterized by intention tremors and cerebellar ataxia and may progress to parkinsonism
What is the molecular basis of fragile X syndrome?
- loss of function of the familial mental retardation protein (FMRP)
- When the trinucleotide repeats in the FMR1 gene exceed approximately 230, the DNA of the entire 5′ region of the gene becomes abnormally methylated. Methylation also extends upstream into the promoter region of the gene, resulting in transcriptional suppression ofFMR1.
- The resulting absence of FMRP is believed to cause the phenotypic changes
What is the molecular basis of symptoms in Fragile X syndrome?
- FMRP is a widely expressed cytoplasmic protein, most abundant in the brain and testis, the two organs most affected in this disease.
- FMRP is an RNA-binding protein associated with polysomes. Unlike other cells, in neurons protein synthesis occurs both in the perinuclear cytoplasm and in dendritic spines. FMRP is first transported from the cytoplasm to the nucleus, where it assembles into a complex containing specific mRNA transcripts. The assembled complex is then exported to the cytoplasm. From here the FMRP-mRNA complex is transported to the dendrites close to the synapse. Not all species of mRNA are transported by FMRP to the dendrites. Only those that encode proteins that regulate synaptic function are so shuttled by FMRP. At the synaptic junctions, FMRP suppresses protein synthesis from the bound mRNAs in response to signaling through group I metabotropic glutamate receptors (mGlu-R).
- In fragile-X syndrome a reduction in FMRP results in increased translation of the bound mRNAs at the synaptic junctions. Such imbalance in turn causes permanent changes in synaptic activity and ultimately mental retardation.
What is the diagnostic test of choice for Fragile X syndrome?
PCR-based detection of the repeats is now the method of choice for diagnosis. With Southern blot analysis, distinction between premutations and mutations can be made prenatally as well as postnatally
A feature unique to mtDNA is ............
What are the general features of mitochondrial disorders?
- mothers transmit mtDNA to all their offspring, male and female;
- however, daughters but not sons transmit the DNA further to their progeny
- Human mtDNA contains 37 genes, of which 22 are transcribed into transfer RNAs and two into ribosomal RNAs. The remaining 13 genes encode subunits of the respiratory chain enzymes. Because mtDNA encodes enzymes involved in oxidative phosphorylation, mutations affecting these genes exert their deleterious effects primarily on the organs most dependent on oxidative phosphorylation such as the central nervous system, skeletal muscle, cardiac muscle, liver, and kidneys
- Each mitochondrion contains thousands of copies of mtDNA, and, typically, deleterious mutations of mtDNA affect some but not all of these copies. Thus, tissues and, indeed, whole individuals may harbor both wild-type and mutant mtDNA, a situation called heteroplasmy. It should be evident that a minimum number of mutant mtDNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease. This is called the “threshold effect.” Not surprisingly, the threshold is reached most easily in the metabolically active tissues
- During cell division, mitochondria and their contained DNA are randomly distributed to the daughter cells. Thus, when a cell containing normal and mutant mtDNA divides, the proportion of the normal and mutant mtDNA in daughter cells is extremely variable. Therefore, the expression of disorders resulting from mutations in mtDNA is quite variable
Most mtDNA genes encode........
What is heteroplasmy?
- Each mitochondrion contains thousands of copies of mtDNA, and, typically, deleterious mutations of mtDNA affect some but not all of these copies.
- Thus, tissues and, indeed, whole individuals may harbor both wild-type and mutant mtDNA, a situation called heteroplasmy
What is threshold effect?
- A minimum number of mutant mtDNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease. This is called the “threshold effect.”
- Threshold is reached most easily in the metabolically active tissues listed earlier
Why the expression of disorders resulting from mutations in mtDNA is quite variable?
During cell division, mitochondria and their contained DNA are randomly distributed to the daughter cells. Thus, when a cell containing normal and mutant mtDNA divides, the proportion of the normal and mutant mtDNA in daughter cells is extremely variable
What are the features of Leber hereditary optic neuropathy?
- It is a neurodegenerative disease that manifests as a progressive bilateral loss of central vision.
- Visual impairment is first noted between ages 15 and 35, and it leads eventually to blindness.
- Cardiac conduction defects and minor neurologic manifestations in some families
What is genomic imprinting?
- At least with respect to some genes, important functional differences exist between the paternal allele and the maternal allele.
- These differences result from an epigenetic process, called imprinting.
- In most cases, imprinting selectively inactivates either the maternal or paternal allele
What is maternal or paternal imprinting?
- Maternal imprinting --> transcriptional silencing of the maternal allele
- Paternal imprinting --> the paternal allele is inactivated.
Imprinting occur in which stage of development?
Imprinting occurs in the ovum or the sperm, before fertilization, and then is stably transmitted to all somatic cells through mitosis
What are the mechanisms of imprinting?
- Differential patterns of DNA methylation at CG nucleotides
- Histone H4 deacetylation and methylation
What are the clinical features of PWS?
mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, and hypogonadism
What is the genetic basis for PWS?
- interstitial deletion of band q12 in the long arm of chromosome 15, del(15)(q11.2q13)
- In most cases the breakpoints are the same, causing a 5-Mb deletion.
- It is striking that in all cases the deletion affects the paternally derived chromosome 15.
Patients with Angelman syndrome are born with a ..................................
deletion of the same chromosomal region of PWS derived from their mothers
What are the features of AMS?
ataxic gait, seizures, and inappropriate laughter, MR
True or False: PWS and AMS are caused by distinct genes on the same region of chromosome 15
What is the molecular basis of PWS and AMS?
- A gene or set of genes on maternal chromosome 15q12 is imprinted (and hence silenced), and thus the only functional allele(s) are provided by the paternal chromosome. When these are lost as a result of a deletion, the person develops Prader-Willi syndrome.
- Conversely, a distinct gene that also maps to the same region of chromosome 15 is imprinted on the paternal chromosome. Only the maternally derived allele of this gene is normally active. Deletion of this maternal gene on chromosome 15 gives rise to the Angelman syndrome.
- Molecular studies of cytogenetically normal patients with the Prader-Willi syndrome (i.e., those without the deletion) have revealed that they have two maternal copies of chromosome 15. Inheritance of both chromosomes of a pair from one parent is called uniparental disomy.
- The net effect is the same (i.e., the person does not have a functional set of genes from the [nonimprinted] paternal chromosomes 15).
- Angelman syndrome, as might be expected, can also result from uniparental disomy of paternal chromosome 15
What is the cause of cytogenetically normal PWS?
What is the genetic basis for PWS and AMS?
- PWS--> paternal deletion/unimaternal disomy
- AMS--> maternal deletion/unipaternal disomy
What does the genetic change result in in AMS?
- In the Angelman syndrome, the affected gene is a ubiquitin ligase that is involved in catalyzing the transfer of activated ubiquitin to target protein substrates.
- The gene, called UBE3A, maps within the 15q12 region, is imprinted on the paternal chromosome, and is expressed from the maternal allele primarily in specific regions of the brain.
- The imprinting is tissue-specific in that UBE3A is expressed from both alleles in most tissues.
- In contrast to Angelman syndrome, no single gene has been implicated in Prader-Willi syndrome. Instead, a series of genes located in the 15q11.2–q13 interval (which are imprinted on the maternal chromosome and expressed from the paternal chromosome) are believed to be involved. These include a gene that encodes small nuclear riboprotein N, which controls gene splicing and is expressed highly in the brain and heart. Loss of small nuclear riboprotein N function is believed to contribute to Prader-Willi syndrome.
How are PWS and AMS diagnosed?
begins with karyotype and methylation studies, followed by fluorescence in-situ hybridization (FISH), and then microsatellite probes to detect uniparental disomy (UPD).
How can PWS recur in the subsequent child?
Mutation or deletion in imprinting center
IQ in PWS is ............
- 40 below the mean
- mild to moderate MR
Why in autosomal dominant disorder some patients might not have affected parents?
- In such patients the disorder might results from a new mutation in the egg or the sperm from which they were derived; as such, their siblings are neither affected nor at increased risk of developing the diseaseThis is not always the case, however. In some autosomal dominant disorders, exemplified by osteogenesis imperfecta, phenotypically normal parents have more than one affected child. This clearly violates the laws of mendelian inheritance. Studies indicate that gonadal mosaicism may be responsible for such unusual pedigrees
What is gonadal mosaicism?
- Gonadal mosaicism results from a mutation that occurs postzygotically during early (embryonic) development. If the mutation affects only cells destined to form the gonads, the gametes carry the mutation, but the somatic cells of the individual are completely normal. Such an individual is said to exhibit germ line or gonadal mosaicism
- A phenotypically normal parent who has germ line mosaicism can transmit the disease-causing mutation to the offspring through the mutant gamete.
- Because the progenitor cells of the gametes carry the mutation, there is a definite possibility that more than one child of such a parent would be affected.
- Obviously the likelihood of such an occurrence depends on the proportion of germ cells carrying the mutation.
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