Lec: 60 Medical Genetics III - Atypical patterns of inheritance and multifactorial disease Flashcards
What is “epigenetics” ?
The study of gene expression changes that are not rooted in DNA changes.
What proteins make up histones?
Two copies each of H2A/H2B, H3 and H4
What are some possible epigenetic mutations of histones?
Acetylation, methylation, and phosphorylation.
What is the basis of unstable mutations?
They’re a function of “unstable repeats” di/tri/tetra/ or pentanucleotides. The repeats over and over create instability which leads to slipped mispairing mutations.
What is a “normal transmitting male”?
A person carrying a gene that has potential to mutate (more so than normal because of the repeats), that can get progressively more unstable and likely to mutate when he passes the gene on to his progeny.
What is a premutation?
An unstable repeat that doesn’t yet manifest as disease but has the potential to cause a slipped mispairing and disease.
What are some diseases of unstable repeat expansion?
Fragile X syndrome, Huntington disease, Friedrich’s ataxia, and Myotonic dystrophy.
What is dosage compensation?
Equalizing the contribution of X-linked genes in males and females.
What is X inactivation?
Random inactivation of one of the X chromosomes in females.
What is the implication of X inactivation with regard to X linked disease?
Because X inactivation is random some genes will activate maternally and some paternally. This leads to a natural mosaicism. Which means x-linked disease are much more variable and detecting carriers of disease biochemically is much more difficult.
The presence of more than one type of mitochondrial DNA due to mutations is known as?
Heteroplasmy
What is the pattern of inheritance of mitochondrial DNA?
Maternal.
Parent of origin gene imprinting is known as?
Genomic imprinting
When are genes imprinted?
During gametogenesis
Deletion of the imprinted gene 15q11-q13 leads to one of two syndromes, what are they and what differentiates them from a genetic perspective?
The two syndromes are Prader-Willi and Angelman. Prader-Willi is the result of the deletion of the paternally imprinted copy of the gene. Angelman syndrome is the deletion of the maternally imprinted copy of the gene.
What are some of the clinical signs of Prader-Willi Syndrome?
Hypotonia, initial failure to thrive, distinctive facial features, mild to moderate mental retardation, hypogonadism, and an eating disorder (obesity).
What are the clinical presentation symptoms of Angelman syndrome?
Hypotonia, seizures, jerky uncoordinated movements, severe mental retardation, unprovoked laughing/smiling, lack of speech. (Mental retardation is more pronounced in this syndrome than Prader-Willi.
The idea that you need a certain quantity of mutant genes to be present before a disease will manifest phenotypically is known as?
The threshold model of multifactorial inheritance.
What relationships qualify as “first degree” and how is this applied to multifactorial and polygenic disorders?
Parents children and siblings. The closer to first degree the relationship the more likely the person is to develop that condition.
What relationships qualify as “Second degree” and how is this applied to multifactorial and polygenic disorders?
Aunts and uncles, nephews and nieces. The closer to first degree the relationship the more likely the person is to develop that condition.
What relationships qualify as “third degree” and how is this applied to multifactorial and polygenic disorders?
Cousins. The closer to first degree the relationship the more likely the person is to develop that condition.
A difference between concordance values for a genetic condition between monozygotic and dizygotic twins indicates what?
That there is a genetic role for development of the disease (as opposed to more of an epigenetic cause).
Less than a 100% concordance values for a genetic condition between monozygotic twins indicates what?
A role for epigenetic factors in the development of disease.
How does an Xchromosome become inactivated?
Inactivation center (XIC) produces XIST (X inactivation transcript) that spreads through entire chromosome, causing compaction of the chromatin to the histones (thus inactivating it without damaging it) to the point you can see it (Barr Body)
Anticipation
Increasing severity of the disease in later generations due to unstable mutations
Why is mitochondrial DNA so prone to mutation when compared to normal DNA in the nucleus?
Mitochondrial DNA does not have the extensive DNA repair capabilities seen in nucleic DNA. It also has a lot of oxygen radicals floating around.
What do mitochondrial DNA mutations usually affect the most?
Tissues that require a lot of energy like muscle, heart, etc.
LHON
Leber Hereditary Optic Neuropathy - Optic nerve degeneration caused by a missense mutation in any of the three genes coding for respiratory enzymes. This is a mitochondrial DNA disorder.
