203 L4 Flashcards

Mutations and disease

1
Q

A mutation is a change in the ——- sequence of ———

This is reflected in the —- and then the —- that we see

Can expect that a change in the ——- sequence of a gene will cause a change in the ——– coded by that gene

New mutations arise in ——– cells and accumulate as we —— or in the ——- when the mutations can be transmitted to the ———-.

If a ——— mutation does not seriously impair an individual’s ability to have ——– it can spread

De novo mutations - variations in DNA sequences result in new mutations. This is rare because most mutations are ————.

If someone has a mutation that neither the mother or father have then it is a — —- mutation.

Use agarose —— ———- to determine if the mutation has been ———- by either parent or occurs in any siblings.

Most disease associated mutations are ————-

Mutations can be positive (selective advantage e.g. 32bp deletion in the human chemokine receptor that confers HIV resistance), neutral, damaging or lethal

A

A mutation is a change in the base sequence of DNA

This is reflected in the mRNA and then the protein that we see

Can expect that a change in the base sequence of a gene will cause a change in the product coded by that gene (protein)

New mutations arise in somatic cells and accumulate as we age or in the germline when the mutations can be transmitted to the offspring.

If a germline mutation does not seriously impair an individual’s ability to have children it can spread

De novo mutations - variations in DNA sequences result in new mutations. This is rare because most mutations are inherited.

If someone has a mutation that neither the mother or father have then it is a de novo mutation.

Use agarose gel electrophoresis to determine if the mutation has been inherited by either parent or occurs in any siblings.

Most disease associated mutations are inherited

Mutations can be positive (selective advantage e.g. 32bp deletion in the human chemokine receptor that confers HIV resistance), neutral, damaging or lethal

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2
Q

Origins of new mutations

Endogenous mutations

Due to ———– errors in DNA ———– and ———-. The ————- mechanism of the cell picks up on these ———–
There is 1 nucleotide change per cell division

Mutagens - the environment

The occurrence of mutations can be ———– by treatment with certain compounds called ———– - physical or chemical (e.g. UV light, smoking)

Most mutagens act directly by virtue of an ability either to damage a particular nucleotide or to become incorporated into the nucleic acid

A

Due to spontaneous errors in DNA replication and repair. The Proofreading mechanism of the cell picks up on these mutations. There is 1 nucleotide change per cell division

Mutagens - the environment

The occurrence of mutations can be increased by treatment with certain compounds called mutagens - physical or chemical (e.g. UV light, smoking)

Most mutagens act directly by virtue of an ability either to damage a particular nucleotide or to become incorporated into the nucleic acid

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3
Q

Chromosome disorders

Have quite pronounced effects

Due to an excess of deficiency of the genes contained in whole chromosomes or chromosome segments = many genes

Due to a change in the number of chromosome

Often occur during the formation of the zygote, often occur within the egg (when we age)

  • Translocations
  • Delections (e.g. cri, du chat syndrome)
  • Duplications
  • Inversions
  • Chromosome loss (e.g. XO = Turner syndrome)
  • Chromosome duplications (e.g. trisomy 21 = down syndrome)

Are rare in live born infants, but occurs about 50% in all spontaneous 1st trimester miscarriages (tested by CGH)

A

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4
Q

Trisomy 13 - Patau syndrome

Due to the error in the cell —— of the —— - non ———–

Results in the ——- having an increased number of ——— - chromosome —– has 3 copies instead of 2

Increasing risk with ———- age (exponential rise after 30 years old)

In 95% of cases of Patau syndrome a ————- is initiated, live births rarely survive beyond 1 year, disruption of ——- and ——- development

Features include - Holoprosencephaly (failure of the ——– to divide properly), ——— defects, dysmorphology, seizures, severe mental retardation

A

Due to the error in the cell division of the egg - non disjunction

Results in the egg having an increased number of chromosomes - chromosome 13 has 3 copies instead of 2

Increasing risk with maternal age (exponential rise after 30 years old)

In 95% of cases of Patau syndrome a miscarriage is initiated, live births rarely survive beyond 1 year, disruption of kidney and heart development

Features include - Holoprosencephaly (failure of the forebrain to divide properly), Heart defects, dysmorphology, seizures, severe mental retardation

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5
Q

Monosomy - 45 XO Turner’s syndrome

Complete or partial —- chromosome monosomy (chromosome lacks its homologous partner)

Lymphedema - swelling of the hands and feet

Gonadal dysfunction - no menstruation

A

Complete or partial X chromosome monosomy (chromosome lacks its homologous partner)

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6
Q

Cri du chat syndrome or 5p monosomy

——- deletion of chromosome ——

90% of cases are not inherited, 10% are balanced translocation

Individuals are fertile and are able to reproduce

A

Partial deletion of chromosome m5p

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7
Q

Single gene (monogenic) disorders

Caused by individual mutant genes

May be recessive or dominant

May be contained in the mitochondrial or nuclear genomes

Usually exhibit obvious pedigree patterns (inheritance through a family)

Individually rare, but are responsible for a significant portion of disease and death

Affects 2% of the population

A

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8
Q

Substitution mutations

Silent mutations
Often occurs in the —– base position. There is —– change in the —- —–. you would only notice this mutation if the gene was —–.

Nonsense mutation Replacement of —— ——- with a ——– codon dramatically causing a reduction in gene ———. Leads to protein ———-.

Missense mutations
Replacement of ——- —– with different —– ——

Conservative: replacement amino acid is ——- = —— effect on function

Non-conservative: replacement amino acid is ———- = more ——– effect on function

A

Silent mutations
Often occurs in the 3rd base position. There is no change in the amino acid. You would only notice this mutation if the gene was sequenced.

Nonsense mutation Replacement of amino acid with a stop codon dramatically causing a reduction in gene function. Leads to protein truncation.

Missense mutations
Replacement of amino acid with different amino acid

Conservative: replacement amino acid is similar = minimal effect on function

Non-conservative: replacement amino acid is dissimilar = more serious effect on function

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9
Q

Molecular pathology

Mutation = Altered ——- = abnormal —- = disease

There is a clear correlation between ——- and phenotype

Sometimes you can use the —– to predict the ——-.

A

Mutation = Altered protein = abnormal function = disease

There is a clear correlation between genotype and phenotype

Sometimes you can use the genotype to predict the phenotype.

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10
Q

Pathogenic mutations occur in:

———- ———- regions (—–)
Majority of recorded pathogenic mutations
Includes non-synonymous mutations

Mutations disrupting —– stability or —– splicing
Mutations in the ——- sequences
10% of total mutations

——— have to be spliced out from the ——- in order to get the correct —— formed, so when things go wrong in that process it can result in ——-.

Mutations affecting —– regulation or dosage
Promotor/enhancer region mutations
1% of total mutations

Gene regulation or dosage - e.g. abnormal amounts of the protein being expressed, protein being expressed in the wrong place

A

protein coding regions (exons)
Majority of recorded pathogenic mutations
Includes non-synonymous mutations

Mutations disrupting RNA stability or RNA splicing
Mutations in the intronic sequences
10% of total mutations

Introns have to be spliced out from the mRNA in order to get the correct protein formed, so when things go wrong in that process it can result in disease.

Mutations affecting gene regulation or dosage
Promotor/enhancer region mutations
1% of total mutations

Gene regulation or dosage - e.g. abnormal amounts of the protein being expressed, protein being expressed in the wrong place

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11
Q

What is a frameshift mutation?

A

Insertion or deletion of a base or bases.

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12
Q

Frameshift mutations

Results in a different sequence of ——- —– from the point of ——- or ——-, usually ending in a premature ——- of the ——.

Usually when they occur in a multiple of ——– they are —– severe, as they don’t change the ———- frame

Usually associated with severe ———.

A

Results in a different sequence of amino acids from the point of deletion or insertion, usually ending in a premature truncation of the protein.

Usually when they occur in a multiple of 3 they are less severe, as they don’t change the reading frame

Usually associated with severe phenotypes.

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13
Q

The effect of the premature protein truncation (smaller protein) will depend on:

The ——— of the ———– product

The extent of the ——–

The ———- importance of the missing ——- ——-.

A

The stability of the polypeptide product

The extent of the truncation

The functional importance of the missing amino acids

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14
Q

Autosomal recessive inheritance

Appears mainly in the ——- of the proband, not in the —–, —— or other relatives

Males and females are —– affected

Parents of the affected child are ———— carriers of the —— allele so are unaffected.

The risk for each sibling of the proband is — in —-.

Not many people are ——– because you need —– copies of the gene to have the condition.

Name an disease that results from autosomal recessive.

A

Appears mainly in the siblings of the proband, not in the parents, offspring or other relatives

Males and females are equally affected

Parents of the affected child are heterozygous carriers of the mutant allele so are unaffected.

The risk for each sibling of the proband is 1 in 4.

Not many people are affected because you need 2 copies of the gene to have the condition.

Name an disease that results from autosomal recessive

Cystic fibrosis

Rare

Carriers are not clinically recognisable

Common in caucasian children

In heterozygotes the normal copy of the gene creates enough good protein to compensate.

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15
Q

Autosomal dominant inheritance

The ——- usually appears in every generation, each affected person has an affected ——–.

Any child of affected parent has —–% risk of inheriting the trait

————- normal family members do not transmit the ——— to their children.

Males and females are —– affected.

Autosomal dominant disease:

myotonic dystrophy
Severity of phenotype increases with each ——–.

A

The phenotype usually appears in every generation, each affected person has an affected parent.

Any child of affected parent has 50% risk of inheriting the trait

phenotypically normal family members do not transmit the phenotype to their children.

Males and females are equally affected.

Autosomal dominant disease:

myotonic dystrophy
Severity of phenotype increases with each generation.

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16
Q

X-linked recessive inheritance

Males have a single — chromosome

Females have two —, one of which is ————.

The incidence is much higher in ——- than in ———-.

Heterozygous ——- are usually ———-/mildly ——- due to random —- ———–.

An affected —— will pass on the gene to all of the daughters, who will be ——-.

The gene is normally never transmitted directly from the —– to the —— because they inherit the —–.

The gene may be transmitted through a series of carrier —-.

e.g. Androgen insensitivity syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Hamophilia.

A

Males have a single X chromosome

Females have two X’s, one of which is inactivated.

The incidence is much higher in males than in females.

Heterozygous females are usually unaffected/mildly affected due to random X inactivation.

An affected male will pass on the gene to all of the daughters, who will be carriers.

The gene is normally never transmitted directly from the father to the son because they inherit the Y.

The gene may be transmitted through a series of carrier females.

e.g. Androgen insensitivity syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Hamophilia.

17
Q

Random X-inactivation

Within each cell you can get the random ———– of — of the two —- chromosomes

This means that you can get enough of the —— product to not see the phenotype. As a result the disease is ——- in ———- females.

A

Within each cell you can get the random inactivation of 1 of the two X chromosomes

This means that you can get enough of the good product to not see the phenotype. As a result the disease is milder in heterozygous females.

18
Q

X-linked dominant

Affected males with normal mates have no affected —- and no normal ——–.

Male and female offspring of ——- carriers have a —% risk of inheriting the phenotype.

Affected ——- are about twice as common as affected ——, but the affected ——– usually have a milder disease.

E.g Retinitis pigmentosa, Rett syndrome and vitamin D resistant rickets, congenital generalized hypertrichosis.

A

-linked dominant

Affected males with normal mates have no affected sons and no normal daughters.

Male and female offspring of female carriers have a 50% risk of inheriting the phenotype.

Affected females are about twice as common as affected males, but the affected female usually have a milder disease.

E.g Retinitis pigmentosa, Rett syndrome and vitamin D resistant rickets, congenital generalized hypertrichosis

19
Q

Y-linked dominant

Affects only males

Affected males always have an affected father (unless there is a sporadic mutation

All sons of an affected man are affected

Example - non obstructive spermatogenic failure due to mutations in USP9Y

A

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