1 Disease Causing Abnormalities Flashcards
Degeneracy of genetic code
Some AAs have more than one nucleotide codon specifying during protein synthesis
No ambiguity
A codon will only encode one protein
Synonymous vs non-synonymous substitution
Synonymous (silent) substitution - mutation specifies same AA as original codon - transition at 3rd position
Non synonymous substitution - trans version causes one AA to be replaced by another (missense)
Missense - tranversion (prymidine —> purine) A - C or G - T
minimal to severe adverse effects
Nonsense mutation - An AA specifying codon is replaced by a stop codon (UAA, UAG, UGA)
Start and Stop codons
START: AUG (methionine)
STOP:
UAA
UAG
UGA
Frameshift mutation
May indirectly Lead to premature termination codon
Sequence of coding nucleotides that is not a multiple of three is deleted or inserted -> shifting translational reading frame -> in-frame premature termination codon
Involve deletions or insertions at the DNA level but they can also occur from some mutations that produce altered splicing such as intron retention
Types of chromosome abnormalities
Germ cell (constitutional) - present in all nucleated cells, present in very early development
Somatic (acquired) abnormality - present in only certain cells or tissue of a person
Subdivided into 2 categories:
Structural - arise through chromosome breakage events that are not repaired
Numerical - changes in chromosome number that often arise through errors in chromosome segregation
Structural abnormalities
Deletion - 2 breaks, incorrect joining fragments can result in chromosome being lost
Inversion - switched around
Ring chromosome - circular chromosome
Structurally abnormal chromosomes with a single centromere can be stably propagated through successive rounds of mitosis (acentric or dicentric cannot)
A centric chromosome (dicentric) - will not normally segregate stably at mitosis and eventually be lost
Translocation - 2 different chromosomes each sustain a single break incorrect joining of broken ends can result in the movement of chromosome material between chromosomes
Numerical abnormalities
Euploid - normal chromosomal makeup of an individual (46)
Aneuploid - deviations involving the loss or gain of one or more chromosomes
Trisomy - addition of chromosome (trisomy 21)(47)
Monosomy - deletion of chromosome (turners syndrome)(45)
Polyploid - meant multiples of chromosomes 3n triploids (49) or 4n tetraploids (50)
Aneuploid cells arise through 2 mechanisms
Nondisjunction - paired chromosomes fail to separate
Anaphase Lag -lag is a consequence of an event during cell division where sister chromatids do not properly separate from each other because of improper spindle formation. The chromosome or chromatid does not properly migrate during anaphase and the daughter cells will lose some genetic information
(one sister chromatin is lagging behind/taking too long and will be lost)
How mutation results in disease
Hypomorph - loss of function
Neomorph - gain of toxic function results in change in protein structure, common in cancer (translocations)-> chimeric genes (form through combination of portions of two or more coding sequences to produce new genes)
Nonsense frameshifting splicing mutations -> premature termination codon -> pathways to degrade mRNA -> no protein
Neomorph
The mutant gene product may acquire an altered function or occasionally a new function that is harmful in some way causing cells to die or behave inappropriately
Gain of function mutation -> common in cancer, many arise from chromosomal translocations -> chimeric genes
Loss of function and gain of toxic function quite often involve a change in protein structure
Pathogenesis arising from protein misfolding
Point mutations -> change in protein structure -> disease
For proteins to function correctly they need to fold properly so that they can bind the appropriate interacting molecules
In a hydrophilic environment proteins fold up with the hydrophobic AAs located in the interior and hydrophilic AAs on surface
Modifier genes
The synthesis of alpha and beta globin chains in the Hb is normally tightly regulated to ensure a 1:1 production ratio
Mutated in HB(B) -> reduced production of b-globin chains -> relative excess a-globin chains
The excess of a-globin -> aggregate andprecipate -> death of HSC -> ineffective production of RBCs
A mutationcausing a reduced output of a-globin chains reduces the globin chain imbalance -> production of more RBCs -> Modifier effect
Environmental factors
In some disorders expression of the disease phenotype depends very significantly on environmental factors that may act at different levels:
At a distance (external radiation)
By direct exposure (harmful chemicals we ingest)
By contact with microbes and toxins
** environmental facts especially important in triggering cancers
Turner Syndrome
Mutation: 45, X
Genetic Mechanisms: whole chromosome monosomy- only one that is compatible with postnatal life in humans
1-2500 live births female
Clinical features: girls with short stature, primary ovarian failure, cubits valves, webbed neck, broad chest with wide spaced nipples and angulated nails
Most important structural abnormality: coarctation of the aorta and “horseshoe” kidney
No identifiable features at birth, girls with unexplained short stature have karyotype performed
Klinefelter syndrome
mutation: Male disorder 47, XXY
Genetic Mechanisms: insertion of X chromo during formation of reproductive cells in egg or sperm in one of affected persons parents
1-600 newborn males
Clinical features: thin build and disproportionally long arms and legs
Primary testicular failure -> gynecomastia, infertility, small testicles
Increase in frequency of extragonadal germ cell tumors, DVT, PE, mitral valve prolapse, varicose veins, venous ulcers
Down syndrome
Mutation: Whole chromosome aneuploidy- trisomy 21 (95%)
Genetic mechanisms: insertion of chromo 21 (47)
Clinical features: fallen in of facial profile, small nose, epicanthal folds, brush field spots, short fifth fingers, wide gasp between first and second toes, single transverse palmar creases
Variety of neurological problems - lower then average IQ, Alzheimer’s disease, low muscle tone (hypotonia) and vision and hearing problems, congenital heart malformations
Overall indecency of leukemia is about 11 fold > general population
Maternal age effects in Down syndrome
Nondisjunction causes gamete to have extra copy of chromosome 21 - occurs at either meiotic Divison in spermatogenesis or oogenesis
70% of cases occurs in meiosis I in mother - consequence of extremely long duration of meiosis I in females (begins in thirst month of fetal life but is arrested and not completed until after ovulation
Maternal age:
<25 1/1600 25-29 1/1100 30-34 1/700 35-39 1/250 40-42 1/80 >42 1/40
Codon and anticodon
Codon: sequence of 3 or more nucleotides that form genetic code
Anticodon: sequence of 3 nucleotides forming a unit of genetic code in transfer RNA molecule corresponding to a complementary codon in mRNA
Transition vs transversion
Transition: purine - purine or pyrimidine to pyrimidine
Purine to purine (A-G or G-A)
Pyrimidine to pyrimidine (C-T or T-C)
Transversion:
purine - pyrimidine (A-C/T or G-T/C)
Pyrimidine to purine (C-A/C or T- A/C)
Purine and prymidine
Purine - A G
Pyrimidine - C T
Translocation
If 2 different chromosomes each sustain a single break incorrect joining of the ends can result in movement of chromosomal material between chromosomes
Factors that contribute to poor phenotype-genotype correlations
Modifier genes
Environment
