Genetics-Atypical Inheritance Multifactorial Disorders Flashcards
Changes in gene expression without changes in gene DNA
Epigenetics
Levels of DNA folding
1) Formation of nucleosome folding around histone core (11nm fiber) 2) Further condensation into the chromosome seen in metaphase.
Heterochromatin vs. euchromatin
Heterochromatin is dark in the nucleus and euchromatin is light (being actively transcribed)
2 types of heterochromatin
1) Constitutive (same in every cell, like the Y chromosome and areas around centromere) 2) Facultative (varies in different cell types)
What makes up the protein core around which nucleosomes form?
8 histones, with 2 com pies of H2A, H2B, H3 and H4
What types of post-translational modification can histones undergo? How do these affect expression?
Acetylation, methylation, phosphorylation. Modifications make the nucleosome more loose or more tight, regulating accessibility to genes and thus regulating gene expression.
What neurologic disorder is fatal in males and causes altered expression of genes that affect brain function in females?
Rett syndrome: MECP2 protein mutation. Normally this protein binds to methylated silenced genes in the CNS. It ensures these genes are silenced in the CNS. When it is mutated some of the silenced genes become expressed.
What are the 3 classes of genes on the inactivated X chromosome?
Completely inactivated genes, not inactivated genes (pair with Y in meiosis) and some genes completely or partially escape activation
How does X inactivation occur?
X-inactivator center (XIC) codes for X inactive specific transcript (XIST RNA). XIST RNA covers the entire X chromosome and alters chromatin structure, methylates DNA and forms Barr bodies (compacted DNA seen on EM). This inactivates all genes.)
What genetic principle is illustrated by this image from a child with incontinentia pigment? How do you know this child is a female?
It is an x-linked disorder. Females have 2 X chromosomes so you get random inactivation of the diseased chromosome that produces a mosaic. In males, the entire body expresses the diseased chromosome because there is only one X.
Why are X-linked diseases more variable in females?
X inactivation is random and they can have more or less expression of the diseased chromosome based on the random assortment.
What exceptions are there to X inactivations?
Turner’s syndrome (only one X) it is not inactivated. Triple X, 2 are inactivated. Structurally rearranged X chromosomes with autosomes are usually inactivated.
What is the mechanism by which trinucleotide expansion occurs?
Slipped mispairing. DNA loops out during replication and is repeated within the loop.
Friedreich ataxia mutation
AR unstable GAA repeats in the intron
Why are you concerned about people with permutations in trinucleotide repeats even though it does not cause them disease?
It is likely to be increased in the next generation and cause disease
A patient presents with muscle wasting, myotonia, cardiac arrhythmia and cataracts. That worsens with age. What is causing her condition?
AD mutation in DMPK causing unstable CTG repeats. This causes RNA hairpin formation in the nucleus that cannot be broken. It then attracts all of the RNA-binding proteins that are needed for splicing, and other RNAs that need to be spliced don’t get spliced. This causes Myotonic Dystrophy (DM1) and is a gain of function mutation.
How would a pedigree of fragile X syndrome appear?
Daughters of normal transmitting males have a high chance of having an affected male.
A 14 year old boy presents with rapidly deteriorating central vision over the past 3 weeks. He has a family history of this condition and the pedigree is shown below. What is causing his condition?
Leber Hereditary Optic Neuropathy (LHON). This missense mutation in genes encoding respiratory enzymes in the mitochondria causes optic nerve degeneration. Note the mitochondrial inheritance pattern.
What do you call a cell with two different types of mitochondria within it due to ease of mitochondrial mutations?
Heteroplasmy. Since this separation of mitochondria is random, you get variable expression of disease in different people.
A child presents with mitochondrial myopathy, deafness, dementia and myoclonic epilepsy w/an abnormal EEG. The inheritance pattern is shown below. What is the diagnosis?
Myoclonic epilepsy with ragged red fibers (MERRF). Note the varying level of severity due to mitochondrial heteroplasmy in cells.
A patient presents with hypotonia, initial failure to thrive, distinctive facial features, moderate mental retardation, hypogonadism and obesity. What chromosomal abnormalities can cause this condition?
Prader-Willi syndrome. This is due to a deletion on the paternal chromosome 15 imprinted region. Additionally, this could happen if both maternal chromosomes are inherited.
A patient presents with hypotonia, seizures, chorea, severe mental retardation, unprovoked laughter and lack of speech. What chromosomal abnormalities can cause this condition?
Angelman syndrome. This is due to a deletion on the maternal chromosome 15 imprinted region. Additionally this could happen if both paternal chromosomes are inherited.
