619 GLA 8/5 pt 2 Chromosomal Aberrations and Cytogenetic Disroders

4 Trinucleotide Repeat Disorders

huntington disease

myotonic dystrophy type 1

friedreich ataxia

fragile x syndrome

Huntington Disease

trinucleotide repeat disorder, arises due to 40+ CAG triplet expansion in coding region of HTT gene

HTT

gene that codes for huntington protein, contains a CAG repeat

Trinucleotide Expansions

when a repeating sequences of three DNA nucleotides repeats itself more times than usual because of errors in DNA replication

Anticipation

phenomenon of trinucleotide repeat disorders where the number of repeats increases as the genetic mutation passes down through generations, causes the severity of symptoms related to the mutation to become apparent at an earlier age with each new generation

What causes trinucleotide repeat expansion?

DNA polymerase slippage

DNA Polymerase Slippage

mechanism for trinucleotide expansion, when a DNA polymerase encounters repetitive nucleotides it has a tendency to detach and then backtrack and make extra copies when it reattaches

Premutation Range

range of trinucleotide repeats where the individual does not have the disease, but subsequent generations are at a higher risk because the number of repeats is close to pathogenic

Reduced Penetrance of Trinucleotide Repeats

when someone is close to the amount of repeats that causes a condition, but may or may not have the disease

Trinucleotide Repeat Severity

possibility of disease increases with each generation, longer repeat expansions cause more severe interference

Polyglutaminated form of Huntington

forms when HTT is expanded, unstable and prone to degrading into misfolding aggregating fragments, interfere with neuronal function

4 Big Characteristics of Huntington Disease

genetic anticipation

autosomal dominant

involves a trinucleotide repeat number in the HTT gene

shows differences in penetrance

Huntington Disease Inheritance Pattern and Type of Mutation

autosomal dominant, gain-of-function mutation

Why is huntinton’s a gain of function?

because the resulting protein gains a new destructive function

Huntington Disease Clinical Presentation

onset at 20-50, tissue loss in the caudate nucleus and putamen, repetitive and jerky involuntary movements, aggression, depression, dementia

Myotonic Dystrophy Type 1

trinucleotide repeat disorder, CTG trinucleotide repeat expansion occurs in 3’UTR of DMPK gene

causes build-up of toxic materials in muscle cells

Myotonic Dystrophy Type 1 Inheritance

autosomal dominant

Myotonic Dystrophy Type 1 Clinical Presenation

onset in 20-30, myotonia (delayed muscle relaxation), muscle wasting, frontal balding, cataracts, testicular atrophy, cardiac arrhythmias

no cure

Friedreich Ataxia

trinucleotide repeat disorder, occurs in intron, due to GAA repeat expansion on chromo 9 in intronic region of frataxin gene

How does GAA expansion in Friedreich Ataxia impact the frataxin gene?

GAA expansion leads to reduced expression of the frataxin protein, leading to degeneration of nervous tissue in the spinal cord

Is Friedreich Ataxia a loss or gain of function?

loss of function because abnormal splicing sites significantly reduces or eliminates protein production, losing ability to perform normal function

Friedreich Ataxia Inheritance

autosomal recessive

Friedreich Ataxia Clinical Presentation

muscle weakness, loss of deep tendon reflexes, loss of vibratory sense, fall frequently, begins in childhood (5-15) with kyphoscoliosis

Friedreich Ataxia Associated Diseases

diabetes mellitus

hypertrophic cardiomyopathy (commonly causes death)

Kyphoscoliosis

spine deformity that is a common physical finding for friedreich ataxia in childhood

Fragile X Syndrome

develops because of a CGG triplet repeat expansion on the 5’UTR of the FMR1 gene on the X chromosome

How does methylation lead to Fragile X?

the increased CG content from CGG triplet expansion leads to hypermethylation and silencing of FMR1 gene

Is Fragile X a loss or gain of function?

loss of function, because decreased gene expression causes a loss of normal gene function

Fragile X Inheritance

x-linked dominant

silence of FMR1 gene on the x chromo affects males more than femaes

Fragile X Clinical Presentation

most common cause of inherited intellectual disability and autism, second most common cause of genetically associated cognitive dysfunction, hypermobility, macro-orchidism, large jaw and everted ears

Egg Imprinting

in the egg, all of the imprinting is erased and rewritten with the maternal imprint, even if the genes came from the dad

Sperm Imprinting

in the sperm, all of the imprinting is erased and rewritten with the paternal imprint, even if the genes came from the mom

Uniparental Disomy

when a person inherits two copies of the same chromosome from one parent and none from the other, stems from nondisjunction events during meiosis

Uniparental Heterodisomy

when a person inherits two different copies of the same chromosome but from only one parent, caused by nondisjunction during meiosis I

Uniparental Isodisomy

when a person inherits two of the same copy of one chromosome from one parent and none from the other, occurs through nondisjunction during meiosis ii or monosomy duplication

Trisomy Rescue

when a gamete with an extra chromosome combines with a normal gamete with one copy of the gene, and one of the homologous chromosomes is kicked out by another nondisjunction event during the next cycle of mitosis

Monosomy Duplication

a normal gamete is combined with a gamete that is missing the chromosome, duplication of the monosomic chromosome leads to an extra copy of that chromosome being made, resulting in a zygote having two copies of the chromosome (both identical from the same parent)

2 Consequences of Uniparental Disomy

isodisomy increases the risk of inheriting autosomal-recessive conditions

both predispose individuals to genetic disorders via imprinting

Autosomal-Recessive and Uniparental Heterodisomy

there is a 0% chance of offspring developing an autosomal-recessive condition for which their parent is a carrier

What causes PWS and AS?

uniparental inheritance of the 15q11-13 loci

What does the Prader-Willi region of chromo 15 produce normally?

snoRNAs (SNORD115 & SNORD116) involved in processing specific RNA transcripts like certain serotonin receptors

What does the Angelman region of chromo 15 produce normally?

UBE3A, a ubiquitin ligase enzyme responsible for protein degradation in neurons

What is the most likely cause of Prader-Willi Syndrome?

uniparental disomy (when paternal is deleted or mutated)

What is the most common cause of Angelman Syndrome?

a microdeletion of the gene on the maternal chromosome

How could mutation of XY result in Turner Syndrome?

if the SRY portion of the Y gene that encodes for maleness is deleted, then a tuner female would result

Polygenic Feature

feature that is controlled by many genes, where a graph showing the occurrence of that feature having a bell curve

Which is more common, chromosomal aneuploidies for sex chromosomes or autosomes?

sex chromosomes

Genetic Screening Tests

identifies at-risk individuals, rapid way to throw out a wide net

Genetic Diagnostic Tests

take longer to complete but are used when you are looking for something specific

What does gene therapy not do?

gene therapy does not correct congenital malformations once a person is born with them