Molecular,Biochem,Cellular Basis of Genetics 3 Flashcards
What is Osteogenesis Imperfecta?
is a group of inherited disorders that predispose to easy fracturing of bones, even with little trauma, and to skeletal deformity
What are the 2 broad classes of mutations in alpha chains of Type 1 collagen for Osteogenesis Imperfecta?
- Null Mutation
- Missense Glycine Substitution Mutation
What is a null mutation?
Reduces the amount of type 1 collagen made
Give 2 examples of Null mutations
- promoter mutation
- splice signal mutation
What is a Missense Glycine Substitution Mutations?
Mutations that alter the structure of type 1 collagen
*Mutation is worse the closer to the C-terminus of the alpha chain
How do you get the more severe form of Osteogenesis Imperfecta II?
If a Gly is substituted with a Glu, Ala, Val, Asp, or Arg in the C-terminal 2/3 of the molecule
How do you get the more severe form of Osteogenesis Imperfecta I?
substitutions in the N-terminal ¼ of the protein.
In what type of Osteogenesis Imperfecta does the fetus die in utero?
Type 2
Describe clinical features of Osteogenesis Imperfecta I.
- Blue Sclera
- Bone deformity is absent or minimal
- Collagen structure is normal but in few amounts
Describe Type II Osteogenesis Imperfecta.
It is the most severe
Lethal in/after birth
Collagen improperly formed
It is a new mutation (recurrence in the family is low)
Describe Type III Osteogenesis Imperfecta.
Blue Sclera
Progressive bone deformity (Severe)
Collagen is improperly formed
Spinal curvature
hearing loss
Describe Type 4 Osteogenesis Imperfecta.
White Sclera
Mild to moderate bone deformity
Barrel shaped esphagus
Collagen is improperly formed
What type of inheritance is Alzheimer’s disease?
Autosomal Dominant
How common is Alzheimer’s in women?
twice as common
What is the phenotype of Alzheimers?
Clinical features are characterized by a progressive deterioration of memory and of higher cognitive functions, such as reasoning, in addition to behavioral changes
What happens if there is a mutation in PSEN1 or PSEN2?
Mutations in PSEN1 or PSEN2 can lead to a gain of function resulting in increased Ab42 peptide production
For what is PSEN 1 (Presenilin 1) required?
its required for gamma-secretase cleavage of Beta Amyloid Precursor Protein (BAPP) derivatives.
- could be a critical cofactor protein of γ-secretase.
What does presenilin 2 (PSEN 2) do?
Same as PSEN 1
What does APOE (Alipoprotein E) used for?
It is a necessary component for binding VLDLs to their receptors
Why is the e4 allele a major risk factor for?
Developing Alzheimer’s Disease
Why do diseases of mitochondrial DNA occur?
defects of single genes
How are mitochondrial diseases inherited? can males pass the disease?
They are inherited from the mother and males cannot pass it.
What are the 3 types of mutations for mitochondrial diseases?
- –Missense mutations in coding regions of genes that alter
the activity of oxidative phosphorylation proteins.
- Point mutations in rRNA and tRNA genes that impair translation of mitochondrial proteins.
- Rearrangements that cause deletions and duplications in mtDNA.
What is MELAS?
It stands for Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes
What is MELAS?
•MELAS is a condition that affects many of the body’s systems, especially the brain, nervous system (encephalo-) and muscles (myopathy)
What kind of disease is MELAS?
Mitochondrial Disease
What do patients with MELAS have an accumulation of?
They have Lactic Acid buildup or Lactic Acidosis
Patients with MELAS will suffer from a repetition of this symptom….
Stroke-like symptoms that may damage the brain
What is Myoclonic Epilepsy with Ragged-Red Fibers (MERRF)?
is a multisystem disorder characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, and dementia.
When does the onset of MERRF occur?
childhood
What are the 4 features to clinically diagnose MERRF?
- Myoclonus
- Generalized epilepsy
- Ataxia
- Ragged red fibers (RRF) in the muscle biopsy
What is the most common mutation found in over 80% of affected MERRF individuals?
an A-to-G transition at nucleotide 8344
What gene that makes tRNALys is the gene most commonly associated with MERRF?
The mtDNA gene
In MERRF, since mutations are usually present in all tissues, how are these mutations detected?
They are detected in mtDNA from blood leukocytes.
What is an Autosomally transmitted deletions in mtDNA?
It is a syndrome caused by mutations in two nuclear genes
What is the phenotype for Autosomally transmitted deletions in mtDNA?
It resembles chronic progressive external ophthalmoplegia (CPEO) (paralisys of eye muscles)
What is mtDNA depletion syndrome?
disease involving mutations in any of six nuclear genes that lead to a reduction in the number of copies of mtDNA in various tissues.
How is mtDNA depletion syndrome inherited?
Autosomal Dominant
What is so special about Kearns-Sayre syndrome and Pearson syndrome?
They are mitochondrial diseases that are not typically maternally inherited due to heteroplasmy
Leber hereditary optic neuropathy is homoplasmic or heteroplasmic?
homoplasmic
Is MERRF homoplasmic or heteroplasmic?
heteroplasmic
What is the most common mitochondrial DNA mutation ?
3243A>G (normal nucleotide = A, which is substituted by G) in the tRNAleu(UUR) gene
To what different diseases can 3243 A>G (normal nucleotide = A, which is substituted by G) in the tRNAleu(UUR) gene lead?
- diabetes and deafness
- chronic progressive external ophthalmoplegia (CPEO)
- cardio-myopathy or myopathy
Name 1 example of a mitochondrial disease that is multifactorial.
Leber hereditary optic neuropathy
What is Leber’s hereditary optic neuropathy?
Its the rapid, painless bilateral loss of central vision due to optic nerve atrophy in young adults
In LHON, in what sex is there increased penetrance?
Males have a 50%
In LHON, what increases the chances of blindness?
Alcohol and tobacco use
This disease is a trinucleotide repeat of CGG
Fragile X Syndrome
This disease is a trinucleotide repeat of CAG
Huntingtons Disease
This disease is a trinucleotide repeat of GAA.
Friedreich Ataxia
This disease is a trinucleotide repeat of CTG
Myotonic dystrophy 1
What is anticipation?
refers to a pattern of inheritance in which individuals in the most recent generations of the pedigree develop the disease at an earlier age and/or with greater severity as it is transmitted through a family.
What causes anticipation?
the intergenerational expansion of the repeats upon passage from one generation to the next
What causes the slipped mispairing mechanism thought to underlie the expansion of unstable repeats?
an insertion that occurs when the newly synthesized strand aberrantly dissociates from the template strand during replication synthesis.
Once DNA synthesis is resumed, the misaligned molecule will contain one or more extra copies of the repeat
What are the 3 pathological mechanisms that occur in unstable repeat expansions?
Class 1
- Diseases due to the expansion of noncoding repeats that
cause a loss of protein function
Class 2
- Disorders resulting from expansions of noncoding repeats that confer novel properties on the RNA
Class 3
- Diseases due to repeat expansion of a codon
What is impaired in class 1 of the pathologic mechanisms in unstable repeat diseases?
There is impaired transcription of pre-mrna of affected gene
What is Fragile X Syndrome?
Occurs when CGG repeats exceed 200, it triggers excessive
methylation of cytosines in the promoter, thus silencing
transcription from the gene.
When do you have the pre-mutation of Fragile X?
you get FXTAS when you have 60-200 CGG repeats
How does FTAX manifests?
It manifests as late-onset, progressive cerebellar ataxia and intention tremor due to the formation of intranuclear neuronal inclusions.
What does FMRP regulate?
regulates the translation of proteins required for the formation of synapses
What is Freidreich Ataxia?
is the most common inherited spinocerebellar ataxia
How is Freidreich Ataxia inherited?
Autosomal Recessive
What 2 symptoms follow Freidreich Ataxia?
- Cardiomyopathy
- Type 2 Diabetes
What is wrong in Freidreich Ataxia?
There is a defect is in expression of the frataxin gene due to expansion of GAA in intron 1, the GAA repeats result in the inhibition of transcriptional elongation.
Where can Frataxin be found?
In the mitochondria, it is a mitochondrial protein
What does Frataxin do in the mitochondria?
It is involved with iron metabolism
What happens if Frataxin activity is lost?
there will be:
- increased levels of mitochondrial iron
- impaired heme synthesis
- reduced activity of Fe-S-containing proteins (complexes 1-3 of mitochondrial respiratory transport chain)
What is Myotonic Dystrophy 1?
condition with the most pleiotropic phenotype of all the unstable repeat expansion disorders
What are some of the clinical features of Myotonic Dystrophy-1?
- Myotonia (muscle weakness)
- Cardiac conduction defects
- Testicular atrophy
- Insulin resistance
What is the mutated gene in Myotonic Dystrophy-1?
DMPK
What does DMPK code for?
a protein kinase
In Myotonic Dystrophy, there is a repetition of a trinucleotide…what is this trinucleotide? what is the mutated level for this trinucleotide?
CTG in 3’ UTR
more than 50 = mutation
How does the pathogenesis of Myotonic Dystrophy-1 result?
•esult from the binding of RNA-binding proteins to the CUG repeats
What kind of inheritance is Huntington’s Disease?
Autosomal Dominant
What are some of the clinical presentations of Huntingtons’s Disease?
- Chorea
- loss of cognition
- psychiatric abnormalities
What is the trinucleotide repeat for Huntington’s Disease?
CAG
Why is the expansion of the trinucleotide so special in Huntington’s Disease?
Becuase it is a novel function of the huntingtin gene.
Name a striking cellular hallmark of AD.
the presence of insoluble aggregates of the mutant protein in nuclear inclusions
These inclusions may actually be protective as it is the soluble nonaggregated form of the mutant protein that promotes abnormal interactions between the polyglutamine tract and a number of transcriptional regulators to alter the transcription of many genes.
