Imprinting and Epigenetics Flashcards Preview

MS 1 Unit 7 MCP > Imprinting and Epigenetics > Flashcards

Flashcards in Imprinting and Epigenetics Deck (26):

Prader-Willi syndrome (PWS) and Angelman syndrome

-best known microdeletion syndromes
-by karyotype analysis, both appear to have the same interstitial deletion of the proximal long arm of the chromosome 15
-clinically very different


Prader-Willi syndrome

-patients are small and hypotonic at birth, but change within the first year of life to gain weight rapidly
-if not placed on a controlled diet, they can become quite obese due to overeating
-other characteristics include small hands and feet, hypogonadism, and a bad temper
-although they are developmentally delayed, most do well in special education classes
-because of their temper and difficulty in controlling their diet, Prader-Willi patients may be placed in special group homes that provide the proper environment


Angelman syndrome

-severly mentally retarded
-although they are friendly, they usually cannot carry on a normal conversation, and discourse if often punctuated by bursts of inappropriate laughter
-hyperactivity, short stature, microcephaly, seizures, and ataxia


Tests to pick up Prader-Willi and Angelman

-Cytogenetics- Prader Willi 60-65% found, 10-20% Angelman cases
-FISH- 65-85% Prader Willi and Angelman
-Unknown 15-35% Prader Willi and Angelman


Causes of Prader Willi

-deletion on the chromosome 15 inherited from the dad
-not all PWS patients have deletions, some PWS has two copies of the maternal chromosome 15 (maternal uniparental disomy)


Causes of Angelman Syndrome

-deletion present on chromosome 15 inherited from the mom
-therefore, there appears to be a maternal vs. paternal origin difference in the two diseases
-often had two copies of a paternal chromosome 15


Disomy vs Uniparental Disomy

-the presence of 2 chromosomes
-Uniparental Disomy: inheritance of a chromosome or chromosomes from 1 parent to the exclusion of the other parent
-this can't be detected by karyotype because the homologs will look alike, has to be done using molecular probe technology
-furthermore, using molecular studies, it is possible to determine if the chromosomes are from different sources (heterodisomy) or are duplicate copies (isodisomy)


Uniparental isodisomy vs uniparental heterodisomy

-uniparental isodomy- duplication of 1 chromosome from one parent reslting in the lack of heterozygosity
-uniparental heterodisomy- when there are 2 different chromosomes but both come from the same parent, nondisjunction errors


Cystic Fibrosis

-mechanism has been confirmed by molecular analysis of patients
-given the relatively high frequency of CF carriers in the general population, it is not unusual for a couple with no family history
-it is unusual when the child has two copies of the F508 mutation, paternity is as stated and only one parent has that mutation
-if examination of both of the child's chromosomes 7 reveals that he/she is homozygous at all loci on the 7, this is uniparental isodisomy


Deleted trisomy

-some nondisjunction results in trisomy
-can be corrected if 1 of the 3 chromosomes is lost, this loss is randem
-2/3 of time there is biparental heterodisomy, 1/3 time of uniparental heterodisomy



-the differential modification of the maternal and paternal genetic contributions to the zygote resulting in the differential expression of parental alleles during development and is adult


Imprinting: Male and Female Effect

-for some genes or chromosomal regions, it may be important to have a maternal and paternal contribution
-not all genes or all chromosomes
-usually associated with methylation which is an epigenetic modification
-imprinting-lasts one generation
-change occurs at meiosis



-addition of methyl groups to cytosine residues in the DNA
-can occur within a single gene or a group of adjacent genes
-can occur over a portion of a single chromosome
-can occur over the full length of one or more chromosomes
-the pattern of methylation can be different between males and females


Meiotic Imprinting

-all humans are mosaics of chromosomes inherited from their mothers and fathers. A male will pass on male imprinted (or methylated) chromosomes, and a female will pass on female imprinted chromosomes
-although it is acceptable for the somatic cells to be a mosaic of male and female imprinted chromosome, at the time of reproduction, it is essential that the single correct imprint be transmitted to the offspring
-all male gametes need to carry male chromosomes and all female gametes must carry female chromosomes
-one of the functions of meiosis is to reimprint all of the chromosomes that will end up in gametes
-chromosomes in male meiosis will have the imprint stripped and replaced with a male imprint
-female with female
-thus a child should receive an equal allotment of male and female chromosomes


Imprinting Failure

-this process could fail and as diagrammed from the male, some of the chromosomes would retain the female methylation pattern
-thus in the population of male gametes, on average, half would carry chromosomes with a female imprint
-it is therefore possible to have a child with one chromosome from dad and one chromosome from mom, but both chromosomes have a female imprint


Imprinting Mutation

-looking specifically at PWS, molecular testing proved that some individuals had inherited one chromosome 15 from mom and one from dad and there was no deletion
-there is imprinting error such that a grandmaternal chromosome 15 had gone through paternal meiosis without being reimprinted
-the father has transmitted a maternally imprinted chromosome to the child


Mechanism of PWS

-deletion of the paternal chromosome 15 resulting in only maternal alleles in that region
-maternal uniparental disomy with only maternally imprinted alleles
-an imprinting error, where the complement is comprised of one chromosome from dad and one from mom, but the paternal chromosome has a maternal imprint resulting in functionally only maternal alleles


Mechanism of Angelman Syndrome

-deletion of the maternal chromosome 15 resulting in only paternal alleles in that region
-paternal uniparental disomy with only paternally imprinted alleles
-an imprinting error, where the complement is comprised of one chromosome from dad and one from mom but the maternal chromosome has a paternal imprint resulting in functionally only paternal imprint resulting in functionally only paternal alleles


Differences in Parental Imprints on Chromosome 15

-for PWS and AS, the region of interest contains a number of genes, but those of most interest are SNRPN, necdin, and UBE3A
-imprinting results in a different set of genes being expressed in a male as compared to a female
-on the maternal chromosome, the SNRPN and necdin genes are methylated and thus are not transcribed. Only the UBE3A is active
-on paternal chromosomes the UBE3A is inactive, but SNRPN and necdin are active
-in an individual, the correct combination of 2 chromosomes (one maternal and one paternal) results in each of the 3 genes being active and transcribed
-a patient who has a deletion of the entire region on the paternal chromosome, or who has two copies of the maternal chromosome will be missing both the SNRPN and necdin proteins. These proteins are critical for normal development, so in their absence, an individual will be affected with PWS
-AS deficit in UBE3A



-the study of heritable changes in gene function that are not caused by change in the DNA sequence
-modification of transcription that alters gene expression and this phenotype
-this is a normal process required for normal cell function
-change in epigenetic effects can result in up or down regulation of genes and this can result in disease


Epigenetic Modifications

-DNA methylation- results in modification of function or complete inactivation, single gene group of adjacent genes or a whole chromosome
-histone modification- transcription modification
-chromatin remodeling
-act alone or in combination



-stem cells retain the ability to differentiate into any cell type
-as the organism develops, differentiation occurs resulting in different cell types with different functions
-a specific pattern of genes must be active whereas others are inactivated to create specific tissue and organ phenotypes
-mechanisms include DNA methylation, histone modification, remodeling of chromatin structure


Transcription factors

-bind to DNA and alter gene transcription
-can act as an activator or repressor
-bind specifically to enhancer or promoter regions of the DNA adjacent to a specific gene



-small non coding RNAs
-miRNAs bind to mRNA to regulate gene expression
-this can prevent translation or interfere with the translation process
-down regulation of miRNA caused by hypermethylation at the miRNA promotors is reported in a number of tumors
-miR-15a and miR-16-1 are down regulated in leukemia
-down regulation of miR-107 has been linked to pathogenesis in Alzheimer disease
-miR-21 is upregulated in breast cancer
-these present targets for therapy and drug development


Epigenetics and Human Disease

-cancer (breast and ovarian, pancreatic, melanoma, leukemia and lymphoma)
-auto-immune disorders (arthritis, diabetes, multiple sclerosis
-neurodevelopmental diseases (Rett, Coffin-Lowry)
-neurological and neurodegenerative diseases (Fragile X, Alzheimer, Prader-Willi/Angelman, Parkinson, Huntington, epilepsy)


Rett Syndrome

-neurodevelopmental disorder
-affects primarily females
-normal early development followed by arrested development then regression
-disruption of motor functions; problems with control of hands and feet
-intellectual disability
-loss of speech
-variable phenotypes- appears to be partially dependent on the frequency of mutant alleles that are inactivated

-a transcription factor that can activate or repress transcription
-normal function required for maturation of neurons and normal development