Lecture 20 - Genetic Diseases

Front 1

Achondroplasia phenotypes are primarily genetically determined. T/F

Back 1

T

Front 2

–Mental retardation in persons with PKU (phenylketonuria) phenotypes depend on ____ and ____ factors

Back 2

Genetics and environmental

Front 3

lead poisoning is resulted primarily from ____ factors

Back 3

Environmental

Front 4

What are the four types of genetic disorders?

Back 4

1.Chromosomes and chromosome abnormalities
2.Single gene disorders
3.Polygenic Disorders
4.Mitochondrial disorders

Front 5

In chromosomal disorders, typically there is more than one ___ involved

Back 5

One

Front 6

Trisomy 21 aka Down syndrome is an example of what kind of disorder?

Back 6

Chromosomal

Front 7

Single gene disorders are transmitted in a ____ fashion

Back 7

Mendelian

Front 8

How are these diseases inherited?

•Osteogenesis imperfecta -
•Sickle cell anemia -
•Hemophilia -

Back 8

•Osteogenesis imperfecta - autosomal dominant
•Sickle cell anemia - autosomal recessive
•Hemophilia - X-linked

Front 9

Mutated genes of osteogenesis imperfecta

Hemophilia A?

Sickle cell?

Back 9

type I collagen genes COL1A1 and COL1A2

Factor VIII gene

B gloving gene

Front 10

Polygenic diseases
•The most _______ yet still the _______ understood of human genetic diseases

•Result from an interaction of ______ genes, each with a_______effect

•The ________ alleles are common

Back 10

Common, least

Multiple, minor

Susceptibility - A gene mutation that increases an individual's susceptibility or predisposition to a certain disease or disorder

Front 11

Type I and type II diabetes, autism, osteoarthritis are examples of what kind of disease?

Back 11

Polygenic

Front 12

What is a polymorphic marker

Back 12

A polymorphic marker is a DNA sequence on a chromosome that is used in the identification of cells, individuals or species. It can also be described as the variations arise, due to mutation or alteration in the genomic loci that are observable.

Front 13

A polymorphic marker

A marker that is frequently
_____ in the population

One can therefore distinguish the two copies of a gene that an individual inherits

They are not themselves _______ they simply mark ______ points in the genome

Back 13

Heterozygous

Pathogenic , specific

Front 14

What are the polymorphic markers used in mapping studies

Back 14

Microsatellites
Snps
Variable number tandem repeats (VNTRs)

Front 15

What is a vntr?

Back 15

Changes in numbers of repeated DNA sequences arranged in tandem arrays

location in a genome where a short nucleotide sequence is organized as a tandem repeat. These can be found on many chromosomes, and often show variations in length between individuals. Each variant acts as an inherited allele, allowing them to be used for personal or parental identification

Front 16

Micro satellites are a specific type of vntrs that are ___-___ bps in length

They are known as _____ or ______

The most widely used micro satellites are what?

Back 16

1-6

Short tandem repeats STR

Simple sequence repeats SSR

CAn microsatellites

Front 17

SNPs
A polymorphism due to a base _______ or
the ---- or ---- of a single base

Back 17

Substitution, insertion, deletion

Front 18

After finding the marker, the next step is to define the ...

Back 18

maximal region
of linkage

Front 19

And then?


Hint: ensemble.org

Back 19

Make a list of the genes within the interval

Front 20

And thennnn?

Back 20

Find the mutation

Target candidate genes within the interval
or Target all genes by DNA sequencing

Front 21

Two important considerations for single-gene disorders

______ heterogeneity and ______ heterogeneity

Back 21

Allelic and locus

Front 22

•Allelic heterogeneity
–The existence of many different disease-causing ______ at a locus

•Locus heterogeneity
–Determination of the same disease or phenotype by mutations at different ____

Back 22

Alleles,

Loci

Front 23

Polygenic diseases are common or rare?

Unrelated affected individuals share
________ risk alleles

Back 23

Ancestral

Front 24

A polygenic pedigree has no clear ________ pattern

Back 24

Inheritance

Can have effected individual with no effected parents

Effected person joining family emphasizes the common nature of the disease

Front 25

Summary


•Mapping single gene disorders
–Use clues
–If none, use...
•A large pedigree
•Several smaller pedigrees - but beware of _____heterogeneity
–DNA sequence analysis of linked region

Back 25

genome-wide linkage analysis, locus

Front 26

•Mapping polygenic disorders
–Model-free genome-wide linkage analysis
•Now being superseded by genome-wide a-------- analysis
–Functional analysis of associated polymorphisms within the refined genomic interval

Back 26

Association

Front 27

Dr. Alois Alzheimer used staining and discovered what in his patients bwain?

Back 27

Plaques and neurofibrillary tangles

Front 28

What is the most common cause of dementia. What%?

Back 28

Alzheimer's, 70

Front 29

Two areas of extreme shrinkage of the brain in Alzheimer's disease

What's enlarges?

Back 29

Hippocampus, cerebral cortex


Enlarged ventricles

Front 30

Neurofibrillary tangles

The microtubule-associated protein ____ gets ____________ in Alzheimer’s disease leading to intracellular neurofibrillary tangles, a histological hallmark of the disease.

Back 30

Tau, hyperphosphorylated

Front 31

Hyperphosphorylation results in the self-_______ of tangles of paired ______ filaments and ______ filaments, which are involved in the pathogenesis of Alzheimer's disease.

Back 31

Assembly, helical, straight

Front 32

When misfolded, the otherwise very _______ tau protein can form extremely insoluble aggregates that contribute to Alzheimer’s disease and a number of other neurodegenerative diseases called ________.

Back 32

Soluble, tauopathies

Front 33

Genetics of Alzheimer's disease

Late onset Alzheimer’s Disease
- ---% of AD cases
- Occurs beyond the age of ___
- Only ___ genetically inherited
The ----- allele of the apolipoprotein E gene
is linked with the disease. But only ---% of the
individuals ---------- for this allele develop the disease.

Early onset Alzeimer’s Disease
- Less than --% of AD cases
- Occurs before the age of 65
- Most cases are -------- cases
FAD is inherited in an autosomal _____ way

Back 33

90, 65, partly, ApoE4, 30%, homozygous

Familial Alzheimer's disease (FAD) , dominant

Front 34

FAD is caused by a mutation in at least one of the 3 genes..

Back 34

- Amyloid Precursor Protein (APP)
- Presenilin-1 (PS1)
- Presenilin-2 (PS2)

Front 35

App, ps1, and ps2 is located on what chromosomes?

Back 35

21, 14, 1

Front 36

Age of onset for app?
Ps1? Ps2?

Back 36

50s

20-50

40-50

Front 37

App is what kind of protein?

What two secretaries cut app? What forms as a result?

What is Responsible for the production of amyloid plaques ?

-Plaques build up in spaces between ----- cells

Back 37

Integral membrane

Beta and gamma secretase: beta secretase is BACEand gamma secretase is ps1/ps2

Result is toxic AB(beta) oligomer, these are responsible for amyloid plaques

Nerve

Front 38

High amounts of Aβ forms plaques in between nerve cells and causes cell death

Cell death occurs due to ------ dysfunction and can cause vulnerable neurons to excitotoxicity and apoptosis by a mechanism involving disruption of cellular _____ homeostasis

Dysfunctional _____ signaling plays a pivotal role in Alzheimer’s Disease

Back 38

Synaptic, calcium, calcium

Front 39

Presenilin 1 and 2 are both ------- proteins.

Mutations in either can cause ---- onset FAD cases

There are more/less mutations in ps1 than ps2. 185 vs 13

Back 39

Transmembrane
Early
More

Front 40

Mutations in PS1 and PS2 are associated with increased production of Aβ___

Aβ___ is the amyloidogenic form of Aβ that is deposited selectively and ---- in Alzheimer’s disease.

Ab42 is required for amyloid deposition in transgenic mice

Back 40

42, 42, early

Amyloids are insoluble fibrous protein aggregates sharing specific structural traits.

Front 41

What is the second most common neurodegenerative disorder?

Back 41

Parkinson's

Front 42

Parkinson's :


•Causes for disease are both ----and ----

•Disorder of the central nervous system that results from the loss of cells in various parts of the brain, including the ------ -----.

Back 42

Environmental , genetic

Substantia nigra

Front 43

oThe substantia nigra produces ---------, a chemical
messenger responsible for signaling within the brain that allow for coordination of -----.

oLoss of dopamine causes neurons to fire without normal control, leaving patients less able to direct or control their -------.

Back 43

Dopamine, movement, movement

Front 44

Pd occurs after the age of


• Symptoms
slowness of movement, rest tremor, rigidity, anxiety,
depression, disturbance in balance, autonomic disturbance

Back 44

50

Front 45

What is the pathological hallmark of Parkinson's

Back 45

Lewy body or cytoplasmic inclusion body

Front 46

Up to how many genes are linked to pd?

Back 46

18

Front 47

the major protein of the Lewy bodies in PD brain?

Several PD-linked genes play a role in the maintenance of _________ function.

Back 47

SNCA=alpha-synuclein

Mitochondrial

Front 48

Longevity can be heritable?

Age for exceptional longevity?

What is the basis?
-reduced incidence of --- and heart ----
-slowed process of ---- in general

Back 48

Yes

90+

Cancer, heart disease, aging

Front 49

Chances to live 100+ year is -- to -- times higher for siblings of centenarians

Back 49

8 to 17 times higher

Front 50

Change in number centenarians in the Netherlands were mostly men or women?

Back 50

Women

Front 51

Marital status of male and female Dutch centenarians

Men who were or were not married lived longer?

Women who were or were not married lived longer?

Back 51

Men who were married lived longer

Women who were not married lived longer

Front 52

Longevity seems to be only ----- heritable.

The nature of genetic influences on longevity is
probably -------- (ie. Single genes), suggested
by both --------- partitioning of heritability as well
as the class of ----- -------.

As if Exceptional longevity were like a discrete trait.

Back 52

Moderately, non additive, statistical, exceptional longevity

Front 53

What protein is associated with longevity?
What are the alleles?

Back 53

Cetp - cholesterol ester transfer protein

V and v

Front 54

___ higher % of larger lipoproteins (favorable)
____ lower % of larger lipoproteins (unfavorable)

Back 54

VV , vv

Front 55

VV 25% in patients 100 years or greater

vv 8 % in patients 70-73 years old


__ genotype significantly enriched in
those exhibiting the exceptional longevity phenotype.

Back 55

VV

Front 56

Some genes linked with EL

Back 56

LMNA
WRN
TEK
GIP
APOE
CDKN2A/B

Front 57

EL may be the result of thousands of -----, each with a ____ effect.

Back 57

Variants, small

Front 58

What is the most significant and replicated gene in EL?


Despit all of this, what does it explain little of?

Back 58

APOE

Genetic Variability

Front 59

EL is determined by a combo of ______ and _____ alleles.

At extreme ages, correlate to very ____ combinations of genetic variants.

The picture emerging from this analysis is the EL is the result of an enrichment of longevity associated variants that______ the effect of disease risk alleles and contribute to the ------ of morbidity(onset) and/or disability towards the end of very long lives

Back 59

Common, rare

Rare

Counter, compression

Front 60

Park1 mutations give rise to mutations in what protein?

Back 60

Alpha-synuclein (SNCA)