Molecular,Biochem,Cellular Basis of Genetics 3

Question 1

What is Osteogenesis Imperfecta?

Answer 1

is a group of inherited disorders that predispose to easy fracturing of bones, even with little trauma, and to skeletal deformity

Question 2

What are the 2 broad classes of mutations in alpha chains of Type 1 collagen for Osteogenesis Imperfecta?

Answer 2

1. Null Mutation
2. Missense Glycine Substitution Mutation

Question 3

What is a null mutation?

Answer 3

Reduces the amount of type 1 collagen made

Question 4

Give 2 examples of Null mutations

Answer 4

1. promoter mutation
2. splice signal mutation

Question 5

What is a Missense Glycine Substitution Mutations?

Answer 5

Mutations that alter the structure of type 1 collagen

*Mutation is worse the closer to the C-terminus of the alpha chain

Question 6

How do you get the more severe form of Osteogenesis Imperfecta II?

Answer 6

If a Gly is substituted with a Glu, Ala, Val, Asp, or Arg in the C-terminal 2/3 of the molecule

Question 7

How do you get the more severe form of Osteogenesis Imperfecta I?

Answer 7

substitutions in the N-terminal ¼ of the protein.

Question 8

In what type of Osteogenesis Imperfecta does the fetus die in utero?

Answer 8

Type 2

Question 9

Describe clinical features of Osteogenesis Imperfecta I.

Answer 9

1. Blue Sclera
2. Bone deformity is absent or minimal
3. Collagen structure is normal but in few amounts

Question 10

Describe Type II Osteogenesis Imperfecta.

Answer 10

It is the most severe

Lethal in/after birth

Collagen improperly formed

It is a new mutation (recurrence in the family is low)

Question 11

Describe Type III Osteogenesis Imperfecta.

Answer 11

Blue Sclera

Progressive bone deformity (Severe)

Collagen is improperly formed

Spinal curvature

hearing loss

Question 12

Describe Type 4 Osteogenesis Imperfecta.

Answer 12

White Sclera

Mild to moderate bone deformity

Barrel shaped esphagus

Collagen is improperly formed

Question 13

What type of inheritance is Alzheimer’s disease?

Answer 13

Autosomal Dominant

Question 14

How common is Alzheimer’s in women?

Answer 14

twice as common

Question 15

What is the phenotype of Alzheimers?

Answer 15

Clinical features are characterized by a progressive deterioration of memory and of higher cognitive functions, such as reasoning, in addition to behavioral changes

Question 16

What happens if there is a mutation in PSEN1 or PSEN2?

Answer 16

Mutations in PSEN1 or PSEN2 can lead to a gain of function resulting in increased Ab42 peptide production

Question 17

For what is PSEN 1 (Presenilin 1) required?

Answer 17

its required for gamma-secretase cleavage of Beta Amyloid Precursor Protein (BAPP) derivatives.

• could be a critical cofactor protein of γ-secretase.

Question 18

What does presenilin 2 (PSEN 2) do?

Answer 18

Same as PSEN 1

Question 19

What does APOE (Alipoprotein E) used for?

Answer 19

It is a necessary component for binding VLDLs to their receptors

Question 20

Why is the e4 allele a major risk factor for?

Answer 20

Developing Alzheimer’s Disease

Question 21

Why do diseases of mitochondrial DNA occur?

Answer 21

defects of single genes

Question 22

How are mitochondrial diseases inherited? can males pass the disease?

Answer 22

They are inherited from the mother and males cannot pass it.

Question 23

What are the 3 types of mutations for mitochondrial diseases?

Answer 23

1. –Missense mutations in coding regions of genes that alter

the activity of oxidative phosphorylation proteins.

2. Point mutations in rRNA and tRNA genes that impair translation of mitochondrial proteins.
3. Rearrangements that cause deletions and duplications in mtDNA.

Question 24

What is MELAS?

Answer 24

It stands for Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes

Question 25

What is MELAS?

Answer 25

•MELAS is a condition that affects many of the body's systems, especially the brain, nervous system (encephalo-) and muscles (myopathy)

Question 26

What kind of disease is MELAS?

Answer 26

Mitochondrial Disease

Question 27

What do patients with MELAS have an accumulation of?

Answer 27

They have Lactic Acid buildup or Lactic Acidosis

Question 28

Patients with MELAS will suffer from a repetition of this symptom....

Answer 28

Stroke-like symptoms that may damage the brain

Question 29

What is Myoclonic Epilepsy with Ragged-Red Fibers (MERRF)?

Answer 29

is a multisystem disorder characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, and dementia.

Question 30

When does the onset of MERRF occur?

Answer 30

childhood

Question 31

What are the 4 features to clinically diagnose MERRF?

Answer 31

1. Myoclonus 2. Generalized epilepsy 3. Ataxia 4. Ragged red fibers (RRF) in the muscle biopsy

Question 32

What is the most common mutation found in over 80% of affected MERRF individuals?

Answer 32

an A-to-G transition at nucleotide 8344

Question 33

What gene that makes tRNALys is the gene most commonly associated with MERRF?

Answer 33

The mtDNA gene

Question 34

In MERRF, since mutations are usually present in all tissues, how are these mutations detected?

Answer 34

They are detected in mtDNA from blood leukocytes.

Question 35

What is an Autosomally transmitted deletions in mtDNA?

Answer 35

It is a syndrome caused by mutations in two nuclear genes

Question 36

What is the phenotype for Autosomally transmitted deletions in mtDNA?

Answer 36

It resembles chronic progressive external ophthalmoplegia (CPEO) (paralisys of eye muscles)

Question 37

What is mtDNA depletion syndrome?

Answer 37

disease involving mutations in any of six nuclear genes that lead to a reduction in the number of copies of mtDNA in various tissues.

Question 38

How is mtDNA depletion syndrome inherited?

Answer 38

Autosomal Dominant

Question 39

What is so special about Kearns-Sayre syndrome and Pearson syndrome?

Answer 39

They are mitochondrial diseases that are not typically maternally inherited due to heteroplasmy

Question 40

Leber hereditary optic neuropathy is homoplasmic or heteroplasmic?

Answer 40

homoplasmic

Question 41

Is MERRF homoplasmic or heteroplasmic?

Answer 41

heteroplasmic

Question 42

What is the most common mitochondrial DNA mutation ?

Answer 42

3243A\>G (normal nucleotide = A, which is substituted by G) in the tRNAleu(UUR) gene

Question 43

To what different diseases can 3243 A\>G (normal nucleotide = A, which is substituted by G) in the tRNAleu(UUR) gene lead?

Answer 43

* diabetes and deafness * chronic progressive external ophthalmoplegia (CPEO) * cardio-myopathy or myopathy

Question 44

Name 1 example of a mitochondrial disease that is multifactorial.

Answer 44

Leber hereditary optic neuropathy

Question 45

What is Leber's hereditary optic neuropathy?

Answer 45

Its the rapid, painless bilateral loss of central vision due to optic nerve atrophy in young adults

Question 46

In LHON, in what sex is there increased penetrance?

Answer 46

Males have a 50%

Question 47

In LHON, what increases the chances of blindness?

Answer 47

Alcohol and tobacco use

Question 48

This disease is a trinucleotide repeat of CGG

Answer 48

Fragile X Syndrome

Question 49

This disease is a trinucleotide repeat of CAG

Answer 49

Huntingtons Disease

Question 50

This disease is a trinucleotide repeat of GAA.

Answer 50

Friedreich Ataxia

Question 51

This disease is a trinucleotide repeat of CTG

Answer 51

Myotonic dystrophy 1

Question 52

What is anticipation?

Answer 52

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.

Question 53

What causes anticipation?

Answer 53

the intergenerational expansion of the repeats upon passage from one generation to the next

Question 54

What causes the slipped mispairing mechanism thought to underlie the expansion of unstable repeats?

Answer 54

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

Question 55

What are the 3 pathological mechanisms that occur in unstable repeat expansions?

Answer 55

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

Question 56

What is impaired in class 1 of the pathologic mechanisms in unstable repeat diseases?

Answer 56

There is impaired transcription of pre-mrna of affected gene

Question 57

What is Fragile X Syndrome?

Answer 57

Occurs when CGG repeats exceed 200, it triggers excessive ## Footnote methylation of cytosines in the promoter, thus silencing transcription from the gene.

Question 58

When do you have the pre-mutation of Fragile X?

Answer 58

you get FXTAS when you have 60-200 CGG repeats

Question 59

How does FTAX manifests?

Answer 59

It manifests as late-onset, progressive cerebellar ataxia and intention tremor due to the formation of intranuclear neuronal inclusions.

Question 60

What does FMRP regulate?

Answer 60

regulates the translation of proteins required for the formation of synapses

Question 61

What is Freidreich Ataxia?

Answer 61

is the most common inherited spinocerebellar ataxia

Question 62

How is Freidreich Ataxia inherited?

Answer 62

Autosomal Recessive

Question 63

What 2 symptoms follow Freidreich Ataxia?

Answer 63

1. Cardiomyopathy 2. Type 2 Diabetes

Question 64

What is wrong in Freidreich Ataxia?

Answer 64

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.

Question 65

Where can Frataxin be found?

Answer 65

In the mitochondria, it is a mitochondrial protein

Question 66

What does Frataxin do in the mitochondria?

Answer 66

It is involved with iron metabolism

Question 67

What happens if Frataxin activity is lost?

Answer 67

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)

Question 68

What is Myotonic Dystrophy 1?

Answer 68

condition with the most pleiotropic phenotype of all the unstable repeat expansion disorders

Question 69

What are some of the clinical features of Myotonic Dystrophy-1?

Answer 69

1. Myotonia (muscle weakness) 2. Cardiac conduction defects 3. Testicular atrophy 4. Insulin resistance

Question 70

What is the mutated gene in Myotonic Dystrophy-1?

Answer 70

DMPK

Question 71

What does DMPK code for?

Answer 71

a protein kinase

Question 72

In Myotonic Dystrophy, there is a repetition of a trinucleotide...what is this trinucleotide? what is the mutated level for this trinucleotide?

Answer 72

CTG in 3' UTR more than 50 = mutation

Question 73

How does the pathogenesis of Myotonic Dystrophy-1 result?

Answer 73

•esult from the binding of RNA-binding proteins to the CUG repeats

Question 74

What kind of inheritance is Huntington's Disease?

Answer 74

Autosomal Dominant

Question 75

What are some of the clinical presentations of Huntingtons's Disease?

Answer 75

1. Chorea 2. loss of cognition 3. psychiatric abnormalities

Question 76

What is the trinucleotide repeat for Huntington's Disease?

Answer 76

CAG

Question 77

Why is the expansion of the trinucleotide so special in Huntington's Disease?

Answer 77

Becuase it is a novel function of the huntingtin gene.

Question 78

Name a striking cellular hallmark of AD.

Answer 78

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.