PHRM 82400: Exam 4 Study Materials - Lecture 35-36 on Genetic Diseases

what does recessive mean?

effects of a variant allele are observed only in the absence of a normal allele (homozygous)

what does dominant mean?

effects of a variant allele are observed in the presence of a normal allele (heterozygous)

what does autosomal mean?

involves chromosomes 1-22

what does sex-linked mean?

involves x or y chromosomes

what are the chances of the inheritance of an autosomal recessive trait if both parents have the mutant gene?

- 25% chance of having an affected child

- 50% chance of a carrier child

- 25% chance of a noncarrier child

- same probability for male and female children

- unaffected siblings may be carriers (67%)

- all children of an affected parent are carriers

- age of onset is frequently early in life for many conditions

- symptoms tend to be more uniform than with autosomal dominant disorders

what are the chances of the inheritance of an autosomal dominant trait?

- 50% chance of passing the trait to each child

- same probability for male and female children

- unaffected relatives or siblings do not transmit the disorder

- age of onset is delayed for some autosomal dominant diseases (huntington disease; signs and symptoms of the disorder appear later in life)

what does penetrance mean?

how many people who have a mutation in a specific gene show any traits associated with defects in that gene?

- complete = 100%

- incomplete = <100%

what does expressivity mean?

mutations in a gene can give rise to different outcomes in different people

- number

- identity

- extent (severity)

(ranges from complete to minimal)

what is expressivity affected by?

- other genes

- exposure to harmful chemicals or conditions

- environment

- age

what are different consequences of variants?

- pathogenic

- likely pathogenic

- uncertain significance

- likely benign

- benign

what does pathogenic mean?

- responsible for causing disease

- well supported by scientific research

- often referred to as mutations

what does likely pathogenic mean?

- probably responsible for causing disease

- not enough scientific research to be sure

what does uncertain significance mean?

- not confirmed to cause disease

- not enough scientific research

what does likely benign mean?

- probably not responsible for causing disease

- not enough scientific research to be sure

what does benign mean?

- not responsible for causing disease

- strong scientific research to rule out link to disease

how do inherited (hereditary) variants occur?

- passed from parent to child

- present throughout a person's life in virtually every cell in the body

- germline variants: present in the parent's egg or sperm cells (germ cells)

how do non-inherited variants occur?

- occur at some time during a person's life

- not found in every cell in the body

- somatic variants: occur in somatic cells (cells other than sperm and egg cells)

- not passed to the next generation

- can be caused by environmental factors (e.g. UV radiation) or result from an error in DNA replication

how do new (de novo) variants occur?

- found in a child but not either parent (no family history of the disorder)

- may occur in a paren't eff or sperm cell but is not present in any of their other cells OR in the fertilized egg shortly after the egg and sperm cells unite

- variants acquired during development can lead mosaicism

what are the types of genetic variants?

substitutions

- missense mutation

- nonsense mutation

insertions and deletions -> frameshift

- insertion mutation

- deletion mutation

can pathogenic variants occur in areas other than protein coding sequences?

what are the different effects mutations can have on gene activity?

- no effect = neutral or silent

- complete loss of function = amorphic

- partial loss of function = hypomorphic

- gain of function = hypermorphic

- dominant negative = inhibits activity of unmutated protein

- acquisition of a new property = neomorphic

what is an example of an autosomal recessive disease?

cystic fibrosis

what is cystic fibrosis?

- most common lethal genetic disease that affects the caucasian population (1/3200)

- caused by loss-of-function mutations in cystic fibrosis transmembrane conductance (CFTR)

- many different regulations

how does loss of function lead to recessive effect?

- in most cases, the unmutated copy of the gene is not able to make up for the loss of expression of activity from the mutate gene

- no dosage compensation

what are the different effects CFTR variants can have on CFTR?

- people with variants that have partial activity fare better than those with complete loss of function

- variants establish a dose-response relationship

- people with CFTR alleles with 10-20% function have mild CF

what is the effect of ivacaftor in regards to mutations guiding drug discovery?

- increases function of the CFTR protein

- works only with a specific genotype

- improves clinical symptoms

how is autosomal dominant caused by loss of function?

- familial hypercholesterolemia (FH)

- most often caused by mutations in the LDL receptor (LDL-R)

- >3000 pathogenic variants reported

how does loss of function lead to dominant effect?

in most cases, the unmutated copy of the gene is not able to make up for the loss of expression or activity from the mutate gene

- no dosage compensation

what is a disease caused by loss of function leading to dominant effect?

osteogenesis imperfecta

what is osteogenesis imperfecta?

caused by defects in production of collagen

- collagen trimer (2 subunits of a1, 1 subunit of a2)

what is collagen?

- most abundant protein in the body

- provides structure, support and strength to skin, muscles, bones, and connective tissue

what mutation is dominant negative effect typically caused by?

point mutations

how is autosomal dominant caused by gain of function?

LDL receptor (LDL-R) levels are regulated by PCDK9

- binds LDL-R on cell surface

- internalized with LDL-R

- directs LDL-R to lysosome

- LDL-R is completely degraded

- reduces the number of LDL receptors on cell surface

some PCSK9 mutation shave gain of function effect

-

what are the chances of the inheritance of an x-linked recessive trait?

- 50% fhcance of passing the gene to their sons and daughters (daughters are unaffected, males who receive the gene are affected)

- affected males pass mutant gene to all daughters, but do not pass trait to sons

- usually only males are affected (females can be affected if father has trait and has children with a female carrier (rare))

what is an example of an x-linked genetic disease?

hemophilia a and b

what is hemophilia a and b?

joint bleeding, muscle hematoma, soft tissue bleeding

- a = factor VIII

- b = factor IX

what is the incidence of hemophilia a and b?

- a = 1:5000

- b = 1:30,000

what mutations are involved in hemophilia a and b?

- a = inversion and small deletions

- b = missense

how are diseased caused by triple repeat mutations?

- some genes contain repeats of 3 nucleotides

- longer repeats are associated with disruption of gene function

- ~40 diseases associated with triplet repeats (all are associated with neurodegeneration)

what is the mechanism developing fragile x syndrome?

- most common cause of familial mental retardation

- FRM1 gene: located on x chromosome

- FRM1 contains a CGG repeat (>45) in the 5= UTR of FRM!

- repeat expansion can occur in oogenesis (but not spermatogenesis)

- in patients with this disease, the expanded CGG repeats are hypermethylated. methylation then extends upstream into the promoter region, resulting in transcriptional silencing of the FMR1 gene

- the gene product FMRP is a mRNA binding protein and is involved in transport of some mRNAs from the nucleus to the cytoplasm for translation

how is the mitochondria involved in mutations that cause disease?

- have a separate genome

- present in multiple copies/cell

-

diseases caused by mutation in mitochondrial genes are __________

mutations in mitochondrial genes are transmitted to progeny by

how can diseases caused by mutation in mitochondrial genes affect the body?

affect organs that depend most on oxidative phosphorylation

- skeletal muscle, heart, brain

chromosomal abnormalities are __________

approx. one of 200 newborn infants

changes in chromosome number or structure can affect __________

autosomes or sex chromosomes

what are cytogenetic disorders?

disorders characterized by a change in autosome number are more severe (more genes involved) than single gene disorders

what are some common chromosome structure abnormalities?

- translocation

- isochromosome

- deletion

- inversion

- ring chromosome

what is translocation in regards to chromosome structure abnormalities?

transfer of a part of one chromosome to another chromosome

what is isochromosome in regards to chromosome structure abnormalities?

centromere divides horizontally rather than vertically, resulting in two short arms and two long arms only

what is deletion in regards to chromosome structure abnormalities?

what is inversion in regards to chromosome structure abnormalities?

when there are two interstitial breaks in a chromosome, the segment reunites but is flipped

what is ring chromosome in regards to chromosome structure abnormalities?

a variant of deletion

- after loss of segments from each end of the chromosome, the arms unite to form a ring

what are the genetic changes that cause down syndrome?

- trisome 21 type: 47, XX, +21

- translocation type: 46, XX, der(14;21)(q10;q10), +21

- mosaic type: 46, XX/47, XX, +21

what are the genetic changes that cause turner syndrome?

monosomy X

how are diseases causes by genomic imprinting?

- "parent of origin" transmission

- some regions of DNA are turned off (inactivated) in the copy received from the mother or father

where does genomic imprinting occur?

in ovum or sperm, and is then stably transmitted to all somatic cells derived from the zygote

during genomic imprinting, if a region that is turned off in the maternal copy is mutated in the paternal copy, genes in that region __________

will not be expressed

what are examples of a disease involving genomic imprinting?

prader-wili syndrome and angelman syndrome

what are the characteristics of prader-willi syndrome?

- region of chromosome 15 deleted

- deletion inherited from father

- mental regardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism

what are the characteristics of angelman syndrome?

- region of chromosome 15 deleted

- deletion inherited from mother

- mental retardation, ataxic gait, seizures, inappropriate laughter