Biochem Exam 3: Inheritance Of Genetic Diseases

Front 1

List the different types of gene abnormalities that lead to diseases

Back 1

-missense mutation, changes an amino acid in the primary structure (sickle cell anemia)
-nonsense mutation, creates a stop codon, leading to shortened proteins (duchenne muscular dystrophy)
-RNA synthesis/processing mutation, mutation in the promoter of the gene (beta thalassemia), mutation that influences pre-mRNA splicing, intron becomes part of coding sequence
-small deletions/insertions (few bases), can lead to missing or extra amino acids (if the # divisible by 3), can lead to change in reading frame (frame shift mutation)(if not divisible by 3)
-large deletions/insertion, can involve multiple exons or an entire gene (duchenne muscular dystrophy, alpha thalassemias)
-abnormal recombination, exchange of genetic material btwn homologous sequences of chromosomes

Front 2

Explain the diff btwn genotype & phenotype of a disease

Back 2

genotype: the set of alleles that constitute an individual genetic make-up

phenotype: the observable expression of an individual's genotype, expression of the disease

Front 3

Explain what is the difference btwn wild-type heterozygous, homozygous, & compound heterozygous genotypes

Back 3

wild-type: the most common allele in the population

Front 4

What is penetrance?

Back 4

the probability that a variant allele have any phenotypic expression

*if not all individuals w/ a given genotype manifest the phenotype (disease) then the variant allele has reduced penetrance

Front 5

What is expressivity?

Back 5

the severity of the expressed phenotype (mild versus severe symptoms)

*penetrance & expressivity of a disease can be influenced by age, environmental factors or by other genes

Front 6

What is reproductive fitness of a disease?

Back 6

whether or not the phenotype can be transmitted, if it involved infertility, it cannot be transmitted

Front 7

List conditions that increase the incidence of autosomal recessive disorders

Back 7

-consanguinity: union btwn individuals who are second cousins or closer relatives
-Founder effect: isolated population has increased frequency of disease (homozygosity for the variant allele)

Front 8

explain the role of new mutations in autosomal dominant disorders

Back 8

new mutations are frequent causes of autosomal dominant diseases because a mutation in one allele is satisfactory to express the phenotype

*about 50% of neurofibromatosis cases are due to new mutations

Front 9

List single-gene disorders that deviate from Mendelian Inheritance

Back 9

-genomic imprinting
-unstable repeat expansion
(variant allele changes from generation to generation)
-inheritance of mitochondrial DNA
(only maternal mitochondrial DNA is inherited)

Front 10

What is genetic imprinting?

Back 10

-only one parental allele is active
-inactivation of the other allele is directed by an imprinting center & involved non-coding RNA & DNA methylation

Front 11

How does genetic imprinting manifest in Angelman?

Back 11

-paternal region is inactivated by the imprinting center
-deletion of maternal chromosome 15
-symptoms: mental retardation, happy demeanor, balance disorder, speech impairment
(uniparental disomy can also lead to this disease)

Front 12

How does genetic imprinting manifest in Prader-Willi syndrome?

Back 12

-paternal region inactivated by imprinting center
-deletion of paternal chromosome 15
-symptoms: mental retardation, obesity, short stature, hypogondaism
(uniparental disomy can also lead to this disease)

Front 13

How are diseases with unstable nucleotide repeat expansions inherited?

Back 13

premutations (can expand during meiosis into the pathological range)
-the larger the repeat number is the earlier the onset of the disease is

Front 14

How does this inheritance manifest in Huntington disease?

Back 14

-autosomal dominant
-motor abnormalities, personality changes, loss of cognition and death
-characterized by long expansion of CAG trinucleotide in the huntingtine gene (the protein will have a long poly-glutamate sequence inserted)
-affect repeat number of >35
-repeat numbers btwn 29-35 are called premutations

Front 15

How does this inheritance manifest in Fragile X syndrome?

Back 15

-X-linked dominant
-moderate mental retardation
-caused by excessive CGG repeats in the 5'-untranslated region in the FMR1 gene and silences gene
-normal repeat range: up to 60
-premutations: 60-200
-affected: > 200

Front 16

How does this inheritance manifest in Friedreich ataxia?

Back 16

-autosomal recessive
-symptom: spinocerebellar ataxia (incoordination of limb movement, impairment of position & vibratory senses, speech impairment, scoliosis, cardiomyopathy
-caused by excessive AAG repeats in an intron of the frataxin gene (involved in iron metabolism)
-repeat range 7-34
-premutation 34-65
-affected 100-1200

Front 17

Explain the inheritance of mitochondrial diseases

Back 17

-only maternal mitochondrial DNA is inherited (only females transmit)
-maternal mitochondria are randomly distributed to the daughter cells
-expression of a disease phenotype depends on ratio of normal to mutant mtDNA
-mtDNA diseases frequently have reduced penetrance & variable expression

Front 18

List the major characteristics in the inheritance of multifactorial diseases

Back 18

-genes contribute, but doesnt follow Mendelian inheritance
-diseases often demonstrate familial aggregation
-relatives can be discordant even if they share susceptibility genes
-the disease is more common among close relatives & less common in less closely related relatives

Front 19

Explain how twin studies can delineate the role of genetic & environmental factors in a disease

Back 19

-less than 100% concordance btwn identical genetic twins indicates the contribution of environmental factors
-if concordance is higher in identical twins than in dizygotic twins, then the disease has a genetic component

Front 20

Explain how genetic & environmental factors contribute in venous thrombosis

-formation of venous blood clots can lead to pulmonary embolism

Back 20

Genetic- Factor V and prothrombin

Environmental- oral contraceptives (estrogen containing), smoking, prolonged inactivity & trauma

Front 21

Explain how genetic & environmental factors contribute to type I diabetes

-autoimmune destruction of pancreatic islet beta cells leading to insulin deficiency

Back 21

Genetic- major histocompatibility complex (MHC) locus genes, genes responsible for producing cell surface proteins involved in antigen presentation

Environmental- viral infections (fetal rubella), or early exposure to cow's milk

Front 22

Explain how genetic & environmental factors contribute to coronary artery disease

-formation of atherosclerotic plaques in the heart, can lead to blood clots and MI

Back 22

Genetic- diverse range of susceptibilty genes include diff apolipoproteins, LDL receptor, enzymes involved in homocysteine metabolism, coagulation factors, angiotensin converting enzyme

Environmental- diet, smoking, lack of physical activity

Front 23

Explain how genetic & environmental factors contribute to Alzheimer disease\

-fatal neurodegenerative disease w/ progressive dementia

Back 23

Genetic- Apolipoprotein E (E4 isoform)

Environmental- age, sex (females more frequent), brain injury

Front 24

Explain how genetic & environmental factors contribute to lung cancer

Back 24

Genetic- Aryl hydrocarbon hydroxylase gene, belong to cytochrome P450 gene family, genes have high & low inducibility alleles

Environmental- cigarette smoke

Front 25

When can the Hardy-Weinberg law be used to calculate the distribution of genotypes in a population

Back 25

-when the population is large and there is random mating
-allele frequencies remain constant over time because there is not selection against any genotype & departing individuals from the population have similar allele frequencies

Front 26

List conditions when a population's genotype distribution deviates from the Hardy-Weinberg law

Back 26

-stratification (subgroups w/i population mate)
-assortative mating (choice based on trait)
-consanguinity & inbreeding
-heterozygote advantage (positive selection)

Front 27

Abnormal recombination

Back 27

-unequal crossover, btwn mispaired sister chromatids or chromosomes, can lead to large deletions or duplications (hemoglobin alpha gene deletion)
-can occur btwn homologous sequences on the same chromosome
-this can lead sequence duplications or inversions (severe hemophilia A due to the inversion of the factor VII gene, exon 1-22)

Front 28

What is polymorphism?

Back 28

there are two or more relatively common alleles in the population

Front 29

What is hemizygote?

Back 29

a male with a variant allele on his X chromosome

Front 30

Describe the usual and less frequent phenotypes of Neurofibromatosis 1, an autosomal dominant mutation in the neurofibromin gene

Back 30

Usual phenotype: flat, irregular pigmented skin lesions (cafe au lait spots), fleshy benign tumors on skin (neurofibromas), small benign tumors of the iris of eye (Lisch nodules)

Less frequent phenotype: more severe, learning disabilities, CNS tumors, malignant peripheral nerve sheath tumors

*symptom development is dependent on age, penetrance is age dependent

Front 31

Mendelian inheritance

Back 31

-segregation of the alleles
(during meiosis gametes receive only a single copy of a given allele)
-independance of alleles of different genes
(alleles of diff genes are inherited independently, genes that are close to each other on the same chromosome "linked", have a higher chance to be inherited together

Front 32

Mendelian Inheritance patterns

Back 32

Based on the chromosomal location of the trait
-autosomal- usually affects males & females equally
-X-linked- affects males and females at diff ratios
Based on the dominance of the trait
-recessive- only homozygotes are affected
-dominant- both heterozygotes & homozygotes affected

Front 33

diseases w/ increased frequencies due to founder effect:

Back 33

-Ellis-van Crefeld syndrome (dwarfism, polydactily): old order amish
-I-cell disease (lysosomal storage disease): Lac Saint jean region of Quebec
-Type I tyrosinemia (deficient Tyr degradation) : Lac Saint Jean region of Quebec
-Tay-Sachs disease & Gaucher disease (lysosomal glycolipid storage diseases): Askhenazi Jews

Front 34

Describe autosomal dominant disorders

Back 34

-phenotype usually in every generation
-parent of affected child usually affected
-equally affects males and females

*heterozygote parent has 50% probability of having an affected child

Front 35

In incomplete dominant Inheritance the phenotype in heterozygotes is less severe than in homozygotes. Achondroplasia is caused by what mutation?
What are the heterozygote and homozygote symptoms?

Back 35

-Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (gain of function mutation)

heterozygotes: abnormal bone growth, short stature (limbs), large head, characteristic face, usually normal intelligence, usually normal life span
homozygotes: more severe bone deformities, early death

Front 36

X-linked recessive disorders

Back 36

-much higher incidence in males
-may affect heterozygote females depending on pattern of X linked inactivation
-father's cannot transmit to son
-daughters of an affected father are obligate carriers
-isolated cases can be new mutations

Front 37

Females w/ X linked recessive disease

Back 37

-consanguinity increases the chances for a female to become homozygous & express the phenotype
-In heterozygous cases, the normal allele is inactivated during X-inactivation, female only expresses variant allele in some cells (mosaicism)

Front 38

X-linked dominant disorders

Back 38

-no male to male transmission
-daughter of an affected male and a normal female will be affected
-affected females can transfer (50%) to son & daughters
-2X frequent in females
-females have milder symptoms due to mosaicism
*Rett syndrome, Fragile X syndrome, vitamin D resistant rickets

Front 39

Retts syndrome

-X-linked dominant w/ male lethality

Back 39

symptom:
-developmental stagnation
-neurological disability
-characteristic flapping movements of the hand
-females probably survive this condition because of mosaicism

Front 40

Psuedoautosomal inheritance

Back 40

-inheritance of variant alleles in psuedoautosomal regions of sex chromosomes
-male to male transfer**
^due to recombination btwn psuedoautosomal regions

Front 41

Somatic vs germline mosacism

Back 41

somatic- produced in diff lines of somatic cell, cannot be inherited
germline- produced in gametes during meiosis, inherited

Front 42

Osteogenesis imperfecta (autosomal dominant)

Back 42

-father doesnt have phenotype or mutation in his somatic cells
-2 of his children have the phenotype
-can be explained by germline muation

Front 43

Homoplasmy vs heteroplasmy

Back 43

homoplasmy- cell only contains mutated mtDNA
heteroplasmy- cell contains both normal and mutated

Front 44

A heteroplasmic mother will pass the disease to (all/none) of her children

Back 44

all her children

*however expressivity will vary
Ex- Leber hereditary optic neuropathy (LHON), primarily mtDNA NADH reductase deficiency, causes optic atrophy, loss of vision

Front 45

Multifactorial diseases are caused be interaction btwn multiple genes & environmental factors. Genes associated w/ multifactroial diseases called _________.

*Do NOT follow classical Mendelian inheritance

Back 45

susceptibility genes

Front 46

Qualitative vs quantitative traits

Back 46

qualitative- individual either has disease or doesnt
quantitative- measurable parameters that associate w/ the disease (BP, BMI, cholesterol, etc)

Front 47

If 2 related individuals have the same disease they are (concordant/disconcordant), if 2 related individuals do not have it they are (disconcordant/concordant)

Back 47

concordant

discordant

Front 48

what is familial aggregation?

Back 48

diseases w/ multifactorial inheritance frequently cluster in families.
-this is due to genetic material w/i family & environment w/i the family

Front 49

Hardy-Weinber law

Back 49

P & q are two diff alleles
p+q= 1
P^2 + 2pq + q^2

2pq is the frequency of heterozygotes
p^2 is the frequency of homozygous genotype for P allele