Lecture 8 + 9: Genetic Diseases Flashcards
single gene, mendelian traits
-inheritance patterns
-penetrance and expressivity
-sources mutations
-effects of mutations on gene function
-how do variants lead to dominant and recessive traits?
cytogenetic disorders
-down syndrome
single gene disorders with atypical patterns of inheritance are diseases caused by:
-triplet repeat mutations
-mutations in mitochondrial genes
-genomic imprinting
Inheritance patterns of single gene disorders
-recessive
-dominant
-autosomal
-sex-linked
autosomal
involves chromosomes 1-22
Autosomal recessive trait inheritance
-25% noncarrier
-50% carriers
-25% affected
-all children of an affected parent are carriers
-early sge of onset usually
-more uniform symptoms compared to dominant disorders
Inheritance of autosomal dominant trait
-50-50 chance of passing trait to child
-NO carriers
-delayed age of onset
-huntington diseases signs appear later in life
Penetrance
-% of ppl who have certain mutation show traits associated with defects in the gene
-complete=100%
-incomplete<100%
Expressivity
-mutations giving rise to different outcomes in different ppl
-different number, identity, extent (severity)
-range from complete to minimal
Expressitivity is affected by:
-other genes
-Exposure to harmful chemicals or
conditions
-Environment
=Age
Types of variants
-benign
-likely benign
-pathogenic
-likely pathogenic
-uncertain significance
How do variants occur
-inherited
-non-inherited
-new de novo variants
Iherited variants
-from parent to child
-in almost every cell of body thru life
- germline variants present in the parent’s germ cells
Non-inherited variants
-occur at some time during life
-not every cell
-somatic variants
-not passed down
-can be caused by environment
New de novo variants
-found in child but neither parent
-may occur in egg but not be present in other cells or in egg after uniting with sperm
-variants aquired during development can lead to mosaicism
Types of genetic variants
-substitutiions (silent, missense, nonsense)
-frameshift (insertion, deletion)
silent mutations
-redundant amino acids
-no effect on protein function
missense mutation
-wrong nucleotide
-leads to wrong amino acid which will ruin protein
nonsense mutation
-wrong nucleotide
-leads to STOP sequence
-terminates protein early
Frameshift mutations (insertions and deletions)
-lead to incorrect amino acid sequence down the line
Can pathogenic variants occur in areas other than protein coding sequences?
amorphic
loss of function
hypomorphic
partial loss of function
hypermorphic
gain of function
dominant negative
-inhibits activity of unmutated protein
neomorphic
aquisition of new property
Cystic Fibrosis (autosomal RECESSIVE)
-most common lethal disease of white people
-loss of function mutations in CFTR
CFTR variants have different effects on CFTR
-ppl fare better with variants with PARTIAL activity instead of complete loss of function
-variants establish dose-response relationship
-mild CF when CFTR alleles have 10-20% function
Ivacaftor
-increases function of CFTR protein
-works only on specific genotype
-improves clinical symptoms
How does loss of function lead to recessive effect?
-most times, 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 level of expression is required for full activity?
slide 25
How does loss of function lead to dominanr effect?
-osteogenesis imperfecta
-point mutations
-gain of function
Osteogenesis imperfecta
-defects in collagen production
-most abundant protein in body
-collagen trimer
-loss of proa1
-dominant negative effect caused by point mutations
collagen trimer
-2 subunits of a1
-1 subunit of a2
Autosomal dominant caused by gain of function
-LDL receptor levels regulated by PCSK9 which
PCSK9
-binds LDL on cell surface
-internalized with LDLR
-direct LDLR to lysosome
-LDLR completely degraded
-reduces number of LDLRs on cell
PCSK9 gain of function effect:
-increase affinity for LDL-R
-enhance sorting of LDL-R to lysosome
Autosomal dominant caused by loss of function
-familial hypercholesterolemia (FH)
-most often caused by mutations in the LDLR
->3000 pathogenic variants
Inheritance of X-linked recessive
-50% chance of passing gene
-only males are affected
-affected males pass gene to daughter but not to sons
-female can be affected if father has trait and mother is a carrier (rare)
X-linked genetic diseases
-hemophilia A and B:
-joint bleeding, muscle hematoma, soft tissue bleeding
hemophilia A
-factor VIII
-inversion and small deletion mutations
hemophilia B
-factor IX
-missense mutations
-more common
Disease caused by triplet repeat mutations
-Fragile X syndrome
-some genes contain repeats of 3 nucleotides
-longer repeats disrupt gene function
-~40 diseasees all associated with neurodegradations
Fragile X syndrome
-mental retardation
-FRM1 gene on X chromosome gets silenced
-expanded CGG sequence
-methylation
Diseases Caused by mutations in mitochondrial genes are RARE
-mutations in mitochondrial genes are transmitted to progeny by DAUGHTERS, but not sons
-affect organs that depend most on oxidative phosphorylation (muscle, heart, brain)
mitochondria
-separate genome
-multiple copies per cell
-are inherited only from MOTHER
Cytogenetic disorders
-chromosonal abnormalities
-frequent
-change in chromosome number or structure
-can affevt autosomes or sex chromosomes
-disorders characterized by a change in autosome number are more severe (more genes involved) than single gene disorders
Common chromosomal abnormalities
-translocation
-isochromosome
-deletion
-inversions
-ring chromosome
translocation
-transfer of part of one chromosome to another chromosome
isochromosome
-centromere divides horizontally rather than vertically
-results in 2 short arms and 2 long arms only
Deletion (chromosome)
-loss of a portion of a
chromosome
Inversions (chromosome)
-2 intersitial breaks
-segment reunites but is flipped
Ring chromosome
-variant of deletion
-after loss of segments from each end, arms unite to make a ring
Karotype
chromosome map
Chromosome nondisjunction
??slide 40
Genetic diseases with abnormal chromosome numbers
-down syndrome (trisomy 21)
-turner syndrome (monosomy X)
genetic imprinting
-parent of origin transmission
-some reegions of DNA inactivated (silenced) in copy received from mother or father
-maternal/paternal
-occurs in ovum or sperm
-transmitted to all somatic cells from zygote
-if a gene that is turned off in the maternal copy is mutated in the paternal copy, genes in that region will not be expressed
-complex inheritance patterns
Diseases involving genomic imprinting
-Prader-Willi syndrome
-Angelman syndrome
angelman syndrome (from mother)
-region of chromosome 15 deleted
-from mother
-mental retardation
-ataxic gait
-seizures
-inappropriate laghter
Prader-Willi syndrome
-deletion of region of chromosome 15
-from father
-mental retardation
-short stature
-hypotonia
-obesity
-small hands and feet
-hypogonadism
