Genetics 1 Flashcards
Why have genetic factors become more important in determining the patterns of diseases?
we have experienced improved sanitation, nutrition, public health, and treatments
What are some difficulties in determining the prevalence of genetic disorders in populations?
- some disorders are more common in certain ethnic groups or in certain locations
- some recessively inherited disorders are more common in populations with a history of isolation and consanguineous matings
- some diseases that are genetically determined or influenced (cancer, alzheimers, CVD) are usually not manifested until later in life (delayed penetrance)
Are all mutations harmful? When do most mutations occur? What mutation are passed to the next generation?
- can be harmful causing a disease
- can be beneficial leading to adaptation and evolution
- can be neutral
- most occur during mitosis (somatic) or meiosis (germ)
- mutation in germ cells are passed on
- mutation is the source of all genetic variation, good or bad
What mutations does natural selection favor?
favors mutations that are beneficial while decreasing the prevalence of harmful mutations that make successful reproduction less likely
What genes are more likely to be mutated? why? example?
- large genes because they have more DNA
- Duchenne muscular dystrophy is caused by mutation to Dystrophin gene, 2.3 Mb of DNA, all cases are due to new mutations
What is the expected result of mitosis? whats involved? is genetic material exchanged between chromosomes?
- 2 daughter cells with same genetic makeup as parent cell
- 2 copies of each autosomal chromosome- diploid 2n
- involves DNA replication and random segregation of chromosomes to daughter cells
- no exchange of material, no cross over
What are the phases of mitosis?
Interphase Prophase Pro metaphase Metaphase Anaphase Telophase Cytokinesis
What is the chromosome and DNA content in Interphase? What does N and C mean?
- 2N chromosome content (2 X 23 = 46 chromosomes), diploid
- 2C DNA content= amount of DNA included in 23 haploid chromosomes
In S phase, prior to prophase, what happens? What is the chromosome and DNA content?
- DNA is replicated to generate two identical copies of each of the 46 chromosomes
- 2N chromosome and 4C DNA
After mitosis, who is the chromosome and DNA content?
- 2N chromosome
- 2C DNA
What happens in metaphase? What are sister chromatids? What holds them together?
- sister chromatids are condensed and lined up in the center of the cell
- sister chromatids= two copies of replicated chromosomes held together by centromeres
What can be studied by cytogenetics? in what phase?
-one can study the material for karyotyping in metaphase
Where are cells most commonly obtained for karyotyping?
from circulating lymphocytes
Describe the process of karyotyping?
- blood sample is added to a nutrient medium that contain phytohemagluttinin which stimulates T cells to divide
- cells are maintained in this medium for about 3 days
- colchicine is added which causes arrest of the cell cycle in metaphase
- hypotonic saline causes the RBCs to lyse and chromosomes to spread
- cells are fixed onto a slide, then treated with trypsin and stained
What is G banding?
- Giemsa staining
- most commonly used to stain cells in karyotyping
- gives reproducible light and dark bands
What is the most common clinical indications for chromosome analysis?
newborn with multiple congenital malformations or a child with developmental delay
What is an ideogram used for?
the banding pattern of each chromosome is specific and can be shown in a stylized ideal karyotype
What can a karyotype detect?
- changes in chromosome number
- large insertions or deletions (indels)
What is a normal male karyotype?
- 22 pairs of autosomes
- one X and one Y chromosome (Females XX)
What is fluorescent in-situ hybridization (FISH)? What is the process? What is detected?
- combines conventional cytogenetics with molecular genetic technology
- single stranded DNA probe is labeled with fluorochrome and allowed to anneal with its complement DNA
- chromosome specific unique sequence probes can detect micro deletions
- series of probes can paint a particular chromosome to detect complex rearrangements
What are the stable ends of chromosomes?
telomeres
What does the centromere region consist of? Function?
- constricted region where the kinetochores form and spindle microtubules attach
- these are used in metaphase to line up in the middle and then they are pulled apart
The centromere divides chromosomes into what?
long arm (q) and short arm (p)
What chromosomes are acrocentric? What do the short arms consist of? What is the structure of the short arms?
- 13, 14, 15, 21, 22
- consist of genes encoding ribosomal RNA
- regions are decondensed and form stalks with knobs at the ends called satellites
What are the genetic consequences of meiosis?
- reduction of chromosome number from diploid to haploid
- segregation of alleles in meiosis 1
- shuffling of genetic material by random assortment of homologues- law of independent assortment
- recombination between homologues (cross over) to increase genetic diversity
What is the purpose of meiosis?
to reduce the number of chromosomes in gametes (egg and sperm) to haploid 1N, so egg and sperm can combine to form diploid zygotes containing genetic material from both mother and father
What are the phases of meiosis?
- meiotic S phase
- meiosis I and II- chromosome segregation
-have the same phases as mitosis within meiosis I and II
What is the chromosome and DNA content at the end of meiotic S phase? end of meiosis I? meiosis II?
S phase- 2N, 4C
meiosis I- 1N, 2C haploid (2)
meiosis II- 1N, 1C haploid gametes (4)
What is the purpose of meiosis I?
segregate the two homologues (maternal and paternal), which are in the form of sister chromatids
-meiosis 1- reduction division stage
What are the diploid cells at the beginning of meiosis I?
females- oogonia
males-spermatogonia
In males, in meiosis I, how are the cytoplasm and cell divided?
- cytoplasm is divided evenly during cytokinesis
- two cells (spermatids, secondary spermatocytes) of the same size are produced
In females, in meiosis II, how are the cytoplasm and cell divided?
- most of cytoplasm goes to one of the cells, which becomes the egg (oocyte)
- other cell becomes a smaller, non functioning cell called a polar body which gradually degenerates
What happens in prophase I of meiosis?
-homologous chromosomes are paired and the chromatids of the two chromosomes intertwine (chiasma)
What are chiasmata (chiasma)? How many can form? How many recombination events per meiosis per gamete?
- points at which the chromosomes exchange genetic material by crossing over, process involving recombination
- multiple can form, usually 1 on small, 2 on medium, and 3 on large chromosomes
- 49 recombination events
When does the segregation of homologues occur in meiosis I?
anaphase I
When does the segregation of sister chromatids occur in meiosis II?
anaphase II
What causes genetic diversity in meiosis?
- recombination between homologous chromosomes in prophase I causes crossing over and exchange of genetic material
- genetic makeup is different in each of the 4 gametes
- resulting cells have one copy of each autosomal chromosome = haploid (1N, 1C)
What is the purpose of meiosis II? End result in males? females?
- no replication of DNA
- only segregation of sister chromatids to make 4 haploid cells
- males- 4 functional daughter cells
- females- cytoplasm is distributed mostly to one cell which becomes the egg, and polar body
Describe oogenesis? in embryonic life?
- oogonia are derived from primordial germ cells by a process that involves 20-30 mitotic divisions that occur the first few months of embryonic life
- in the first 3 months of embryonic life, the oogonia begin to mature into primary oocytes, which start to undergo meiosis
- primary oocytes are suspended in meiosis I in female fetus and do no complete meiosis I and II until ovulation, when a single secondary oocyte is formed
- this oocyte can be fertilized to form a zygote
Describe spermatogenesis? how long?
- takes 60-65 days
- entering puberty, spermatogonia have undergone about 30 mitotic divisions to become primary spermatocytes
- these become secondary spermatocytes following meiosis I and spermatids after meiosis II
- spermatids develop without further division into spermatozoa
What does increased parent age cause in the offspring?
increased likelihood of genetic conditions in offspring, different kinds
What is increased maternal age associated with? why?
- increased risk of chromosomal abnormalities due to non disjunction or problems with the separation of chromosomes in meiosis I or II
- related to the length of time the primary oocytes remain suspended in meiosis I until ovulation
When does the risk of aneuploidy increase?
increases sharply with maternal age after about 35 years
What is increased paternal age associated with? why?
- increased risk of certain single gene disorders
- due to problems occurring in mitosis
- probably due to large number of cell divisions undergone by primary spermatocytes from puberty throughout adult life
- 35 year old man, these cells have undergone 540 divisions
What happens if mutations occur in individual somatic cells? Early in development?
- can contribute to cancer or lack of function of the cells or tissues in which they occur
- early on, many tissues and organs derived from that cells might be affected
Germline mosaicism?
- if a mutation occurs during embryonic development that affects all or some of the germline, but few or no somatic cells
- this person is not affected by any genetic condition, but can pass the mutation to multiple offspring
- reccurrence risk is difficult to calculate
All females are mosaic for the _______.
X chromosome
The lyon hypothesis (lyonization)?
one randomly selected X chromosomes is inactivated in each cell early in embryonic development (15-16 days of gestation)
Dosage compensation?
ensures that females produce X linked gene products in amounts similar to males
Barr bodies?
very dense chromatin of the inactivated X chromosome
Mechanism of X chromosome inactivation (lyonization)? why do genes at the tip of the short arm remain active
- the X inactivation center (XIC) is located near the middle of the X chromosome
- it contains a gene that produces a non coding RNA, called XIST
- XIST is expressed only from the inactive X
- XIST binds to DNA along the X chromosome, spreading from the XIC outward
- spreading of XIST along the chromosome correlates with the spread of DNA methylation, heterochromatin formation and gene silencing
- genes at tip of short arm remain active:
- pseudo autosomal region
- homologous to distal short arm of Y chromosome
- same gene dosage in males and females
Why do calico cats display the color that they do?
- gene encoding fur color is located on the X chromosome in cats
- female cats that are heterozygous(one black allele, one orange) are mosaics and display the calico trait
What are types of genetic disease:
chromosomal abnormalities?
Mendelian patterns of inheritance?
Non mendelian patterns?
Chromosomal:
- numerical
- structural
Mendelian:
- autosomal dominant
- autosomal recessive
- X linked
- codominant
Non mendelian
- anticipation
- mitochondrial
- multifactorial
What is a euploid?
- cell that has a multiple of 23 chromosomes
- haploid gametes and diploid somatic cells are euploid
polyploid?
- cell that has complete set of extra chromosomes (still euploid)
- triploidy
- tetraploidy
Triploidy? causes?
- 69 XXX
- one of most common causes of miscarriage in first two trimesters
- disomy (fertilization of one egg by two sperm) is most common cause
Tetraploidy?
92 XXXX
-recorded in a only a few live births
Aneuploid?
cell that has addition or deletion of individual chromosomes, usually only one
Monosomy?
- presence of only one copy of a particular chromosome in an otherwise diploid cell
- almost always incompatible with life, only a few live births observed
Trisomy?
- presence of three copies of one chromosome
- more common in live births
Why is trisomy more common in live births than monosomy?
-excess genetic material is more easily tolerated than a deficiency of genetic material
What most often causes aneuploidy?
non disjunction
-most common in trisomy
What is nondisjunction? Result? resulting zygote?
- two members of a chromosome pair fail to disjoin during meiosis I or two chromatids fail to disjoin in meiosis II
- resulting gamete either lacks a chromosome or has an extra one
- on fertilization, they zygotes are either monosomic or trisomic
Error (nondisjunction) in meiosis I?
- gamete has both homologs of one chromosome pair
- upon fertilization, 2 possible zygotes will be trisomic and 2 will be monosomic
Error (nondisjunction) in meiosis II?
- gamete has two copies of one of the homologs of the chromosome pair
- upon fertilization, 1 possible zygote will be trisomic, 1 is monosomic, and 2 are normal
Is nondisjunction in meiosis more common in the mother or father?
- more common in mother
- increases with age
What three trisomies are compatible with live births?
trisomy 21= down syndrome (47 XY, 21+ or 47 XX, 21+)
trisomy 18= Edwards syndrome (47 XY, 18+ or XX)
trisomy 13= Patau syndrome (47 XY, 13+ or XX)
What are the clinical features of trisomy 21?
- decreased intellectual ability (IQ= 25-75)
- severe hypotonia (low muscle tone) in newborns
- congenital cardiac abnormalities (40-50%)
- increased acute leukemia (10-20X increase)
- abnormal immune response with increased risk of serious infection and thyroid autoimmunity
- almost all adults over 40 age develop alzheimers due to excess amyloid precursor protein (APP)
- characteristic facial appearance
What are the causes of trisomy 21?
- 95% due to nondisjunction, maternal, increases with age
- 4% due to translocations(structural rearrangement on chromosome 21, robertsonian)
- 2-4% due to mosaicism(some somatic cells normal, some with trisomy 21, usually milder phenotype)
What are the clinical features of trisomy 18?
- characteristic appearance-prominent occiput
- 50% die within weeks of birth
- 5-10% survive the first year
- marked developmental disabilities more severe than down syndrome
- congenital heart defects (90%)
What are the causes of trisomy 18?
- > 95% due to nondisjunction, maternal, increases with age
- small number due to mosaicism
What are the clinical features of trisomy 13?
- characteristic appearance- cleft lip and palate
- 5% survive first year
- marked developmental disabilities, more severe than down syndrome
- malformation on CNS, epilepsy
- heart defects
- renal abnormalities
What are the causes of trisomy 13?
- 80% full due to nondisjunction, maternal, increases with age
- others due to trisomy of long arm of chromosome 13 due to translocation
4 examples of sex chromosome aneuploidy syndromes?
- Klinefelter syndrome (47, XXY)
- Turner syndrome/monosomy X (45, X)
- Trisomy X (47, XXX)
- XYY syndrome (47, XYY)
What are the clinical features of Klinefelter syndrome (XXY)?
- common cause of primary hypogonadism in males
- most are sterile
- gynecomastia (1/3)- , develops breasts, increased risk of breast cancer
- sparse body hair
- reduced muscle mass
- predisposition for learning disabilities
- IQ usually in normal range, but lower than unaffected siblings
Causes of klinefelter syndrome?
- nondisjunction (equal maternal/paternal)
- 15% mosaic (sterility less likely)
What rare forms of klinefelter syndrome have been reported?
48 XXXY and 49 XXXXY
- male phenotype
- degree of mental disability and physical abnormality increases with each additional X
What is Turner syndrome? What are the clinical features?
- 45 X
- edema of hand and foot in infancy
- webbed neck
- short stature
- 25-50% congenital heart disease
- failure to develop secondary sex characteristics- common cause of amenorrhea (1/3 of cases)
- hypothyroidism
- IQ in normal range, but some have decreased non verbal, visual spatial information processing
What are the causes of turner syndrome?
- karyotypic variation is reflected in variable severity
- absence of X (50-80%, usually paternal X)
- structural abnormalities of X (14%, partial monosomy)
- mosaics (29%)
What is trisomy X? Features? Causes?
- 47 XXX
- usually benign, but may have sterility, irregular menses, mild mental disability
- 90% due to maternal nondisjunction
- females with >3 X chromosomes have been reported
- mental disability and physical abnormality increase with each addition
What is 47 XYY syndrome? Features?
- taller than average
- IQ reduced 10-15 points
- increased incidence behavioral disorders and learning disabilities
How do you count barr bodies? How many barr bodies does a person with klinefelters syndrome have? Turner syndrome? Trisomy X?
- number of barr bodies is always one less than the number of X chromosomes
- klinefelters (XXY)- one barr body
- Turner (45 X)- 0 barr bodies
- Trisomy X (XXX)- 2 barr bodies
If the extra X chromosomes are inactivated, why aren’t people who carry them phenotypically normal?
- because inactivation of the X chromosome is not complete (15% not inactivated)
- tips of short and long arms of X chromosome don’t get inactivated (pseudoautosomal regions)
- the tip of short arm of X is homologous to the distal short arm of the Y, so gene dosage is normally the same in males and females
- when there is an extra X, these genes are now present in 3 copies instead of the normal 2
How much DNA must a chromosomal defect contain in order to be detected by routine banding techniques?
- a large amount of DNA, that contains many genes (2-4 million bps)
- resolution is higher with FISH
Structural changes in chromosomes usually result from what? How do these changes happen? Rate? How does rate increase?
- chromosome breakage followed by loss and/or rearrangement of material
- happen spontaneously at a low rate
- rate increases by exposure to mutagens, including certain chemicals and ionizing radiation
Balanced reciprocal translocation? abnormalities? risks?
- DNA is rearranged, but you still have the correct amount of DNA, no loss of genetic material
- unique to particular family, incidence 1 in 500
- phenotypically normal
- risk depends on chromosomes involved, increased risk of producing abnormal gametes (1-10%)
Robertsonian (centric fusion) translocation? what is it? abnormalities? most common? risks?
- translocation involving two acrocentric chromosomes (13, 14, 15, 21, 22)
- short arm of one exchanges with the long of the other
- DNA is rearranged and lost, large metacentric with a short fragment
- occurs in 1 to 1,000 phenotypically normal people
- most common: 13q14q
- increased risk of producing abnormal gametes
What is a ring chromosome? How does it occur? abnormalities?
- special kind of deletion that is produced when a break occurs at both ends of a chromosome and the ends become fused
- if significant material is lost, phenotypic abnormalities can occur
- ring chromosomes don’t behave normal in mitosis or meiosis, so there are usually serious consequences
Inversions? how does it occur? abnormalities? pericentric vs paracentric?
- a rearrangement that involves two breaks in a single chromosome with reincorporation of the intervening sequence in the opposite orientation
- pericentric- DNA on opposite sides of the chromosome swap sides
- paracentric- piece of DNA on one side of chromosome flips to face other way
- not much genetic material is lost, compatible with normal development
Isochromosomes? how are they formed? abnormalities?
- formed when one arm of a chromosome is lost and the remaining arm is duplicated
- associated with monosomy for genes on the deleted arm and trisomy for genes on the duplicated arm
- most common isochromosome in live births involves the long arm of the X chromosome
Translocation?
a segment of one chromosome is transferred to another
what is the danger of balanced reciprocal translocations in meiosis?
- chromosomes involved in translocation cannot pair properly to form normal bivalents, instead they cluster
- depending on how the chromosomes segregate, there can be chromosome imbalance
What robertsonian translocation can lead to down syndrome? chances?
14q21q
- phenotypically normal parent that is a carrier of 14q21q has 1/3 (live birth) chance of having child with down syndrome
- 2/3 of cases occurred due to the child
- 1/3 of cases are due to a parent carrier
What event leading to down syndrome has the greater recurrence risk? genetic testing uses?
- translocation has greater recurrence
- genetic testing is to confirm the diagnosis for the child and to facilitate counseling for parents
Examples of deletion syndromes? chances? phenotypes? challenges?
- Wolf hirshorn (4p-)
- cri du chat (5p-)
- rare, 1 in 50,000 births
- severe learning difficulties
- failure to thrive
- variable phenotype, not always correlated with specific loss of genetic material
What are micro deletions? how does it relate to Duchenne muscular dystrophy?
- loss of only a few genes located close together
- some boys with DMD also have other X linked disorders due to deletion involving genes next to dystrophin gene (sub microscopic deletion)
Two examples of micro deletions and how they relate to each other?
- Prader willi syndrome (PWS) and Angelman syndrome (AS)
- both associated with deletion of same region on long arm of chromosome 15
- similar incidence (1 in 15,000)
- 70-80% due to deletions
Where is prader willi syndrome inherited? characteristics of the syndrome? behavior?
- inherited from father
- hypotonia- low muscle tone
- short stature, small hands, feet, hypogonadism
- obesity due to hyperphagia- excessive hunger
- mild to moderate mental disability
- behavior- tantrums, stubbornness, compulsive
Where is angelman syndrome inherited? characteristics of the syndrome? behavior?
- inherited from mother
- severe mental disability
- seizures
- inappropriate laughter
- ataxic gait
If angelman and prader willi syndromes are on the same region of the same chromosome, what determines the parent of origin effect?
imprinting error
-methylation of wrong gene inhibits gene expression
What is another explanation for prader willi and angelman syndromes? (20% of cases)
-uniparental disomy- presence of two chromosomes 15 from same parent
How does uniparental disomy happen?
- when there is non disjunction of chromosome 15 during the production of one of the gametes
- trisomy 15 occurs on fertilization, but this would be fatal, so one copy is lost, most of time normal disomy is restored
- uniparental disomy occurs 1/3 of time
heterodisomy? isosomy?
hetero- two chromosomes are the two different homologs from single parent
iso- two identical alleles
What sources of info are available for mendelian patterns of inheritance?
- OMIM- online mendelian inheritance in man
- disease foundations and support groups online
Principle of segregation (mendel)?
- sexually reproducing organisms have genes that occur in pairs, and only these pairs are transmitted to offspring
- describes behavior of chromosomes in meiosis
Principle of independent assortment (mendel)?
-genes at different loci are transmitted independently
genotype?
refers to an individuals genetic constitution at a particular locus
phenotype?
- trait
- refers to actual physical or clinical observations
Factors that affect expression (mendel, 8)?
- new mutation
- gremlin mosaicism
- reduced penetrance
- age dependent penetrance
- variable expression
- allelic heterogeneity
- locus heterogeneity
- pleiotropy
Where are new mutations more common?
- larger genes, risk increases with paternal age
- recurrence risk same as general population
- autosomal dominant disorders, disease limits reproduction
- offspring of affected individual (50% risk)
Reduced penetrance?
- individual with disease causing phenotype doesn’t necessarily exhibit the disease phenotype
- individual can still transmit the disease causing mutation
age dependent penetrance?
- disease phenotype not apparent until later in life, often after reproduction
- increases frequency of a disease causing allele by reducing natural selection
Variable expression? influences?
-degree of severity of disease phenotype
can be influenced by:
- environmental factors
- interactions with other genes (modifier loci)
- different types of mutations in the same gene (allelic hetero)
Allelic heterogeneity?
disease phenotype can be caused by any of multiple different mutations of the same gene
Locus heterogeneity?
- single disease phenotype caused by different genetic loci in different families
- different loci may encode genes whose products participate in the same biochemical pathway, or are different subunits of a protein complex
pleiotropy?
a single gene mutation can have more than one observable effect (different tissues or organ systems)
Why is the difference between dominant and recessive disorders not always readily apparent?
- many autosomal dominant conditions are more severe in homozygous than in heterozygous
- heterozygous recessive disorders sometimes have mild abnormalities
- matings involving homozygous recessive traits can produce pedigrees that look like dominant transmission
- female carriers of X-linked recessive conditions can sometimes show mild symptoms of disease
If two heterozygous individuals for an autosomal dominant disorder mated, what is the risk that the offspring will have the disorder? What about if one partner was homozygous?
- 75%
- 100%
What does the pedigree chart look like for autosomal dominant disorders?
- vertical transmission of phenotype
- no skipped generations
- males and females equally affected
- father to son transmission can occur
What is familial hypercholesterolemia? traits?
- autosomal dominant
- less than 5% hypercholesterolemia is familial
LDL deficiency
- decreased clearance of cholesterol from blood
- allelic heterogeneity- can be caused by >700 different mutations in LDLR gene
- cholesterol levels increased from birth, atherosclerosis
MI in 30-40s in hetero, teens in homozygotes
-women is usually 7-10 years later
Two examples of familial hypercholesterolemia?
- xanthomas- legions characterized by accumulations of lipid laden macrophages
- acrus corneas- opaque, grayish ring at the periphery of the cornea due to deposit of fatty granules in cells of the cornea
What is retinoblastoma? causes?
- autosomal dominant
- most common childhood eye tumor
- 60% caused by somatic mutations, not transmitted to offspring
- 40% inherited (75% new-paternal, 25% inherited)
- carriers of mutation almost always have tumor by age 5
- reduced penetrance- 10% never develop tumor
- example of two hit model of carcinogenesis
incomplete penetrance?
inherited an autosomal dominant disorder from a parent and passed it on to children, but never developed the disease
How is incomplete penetrance explained in retinoblastoma?
- two hit hypothesis
- retinoblastoma (Rb) is a tumor suppressor
- the protein encoded on the one active, non mutated allele is sufficient to regulate a cell cycle checkpoint that helps prevent cancer
- the acquired mutation leads to loss of heterozygosity and total absence of Rb tumor suppressor activity, development of cancer
- if second hit doesn’t occur, individual doesn’t get cancer
How are inherited cancer syndromes usually inherited? tumor suppressor mutations?
- inherited cancer- autosomal dominant
- tumor suppressor- recessive, both copies have to be inactivated in order for phenotype to be expressed
Tumor suppressor gene mutated in retinoblastoma? Li-fraumeni syndrome? Neurofibromatosis 1 and 2? Breast and ovarian cancer? Lynch syndrome?
- RB
- P53
- NF1, NF2
- BRCA 1, BRCA 2
- MSH2, MSH1, MSH6
What is neurofibromatosis type 1? how is it expressed? characteristics?
- autosomal dominant
- variable expression- mild parent can have severe child
- some mildly affected, may not even know they have it
- cafe au last spots
- lisch nodules- benign growths on iris
- few neurofibromas- nonmalignant peripheral nerve tumors
Characteristics of those severely affected by neurofibramotis type 1?
- 100s to 1000s neurofibromas
- benign tumors of optic nerve
- learning disabilities
- hypertension
- scoliosis
- malignancies
Causes of neurofibomatosis type 1?
- NF1 gene is very large and has high mutation rate
- 50% of cases are due to new mutation
What is achondroplasia? how does it happen? characteristics? penetrance? risk?
- autosomal dominant
- most common cause of genetic short stature
- heterozygotes have reduced stature but normal intelligence and nearly normal lifespan
- homozygotes usually die in infancy due to respiratory failure
- 100% penetrance
- 80% are due to new mutations of fibroblast growth factor receptor 3
- risk increases with paternal age
What is marfan syndrome? causes?
- autosomal dominant
- 1 in 10,000 north americans
- disease in 3 major systems (pleiotropy)- ocular, skeletal, cardiovascular
- most caused by mutation of fibrillin- connective tissue protein
- allelic heterogeneity - 100s different mutations identified
Characteristics of autosomal recessive disorders?
- heterozygous carriers are more common than affected homozygotes
- parents of affected individuals are usually both carriers
- disease may be seen in multiple siblings, but usually not in earlier generations
- males and females are equally affected
- 25% of offspring of two carriers will be affected
- new mutations can occur, but are not clinically apparent
- consanguinity is more common in pedigrees with rare recessive disorders
- quasidominant or pseudodominant inheritance
What is quasi dominant or pseudo dominant inheritance?
-mating between homozygous affected and heterozygous carrier= 50% offspring affected
What is cystic fibrosis? causes?
- autosomal recessive
- euro americans affected most often (1 in 20 US white carriers)
Causes:
-mutation of CFTR gene (cystic fibrosis transmembrane conductance)- encodes ATP dependent chloride channel in apical membrane of epithelial cells
- over 1000 different mutations identified, most are rare (allelic heterogeneity):
- over 60% are homozygous for F508
- 35% compound heterozygotes, one F508 allele and a different CFTR mutation on the other allele (mild phenotype)
clinical features of cystic fibrosis?
- pleiotropy
- pancreatic insufficiency (85%)
- meconium ileus (15-20% newborn)
- high levels of chloride sweat
- male sterility due to absence or obstruction of vas deferent (95%)
- pulmonary disease is major cause of morbidity and mortality
What is most common lethal disease that affects caucasians?
cystic fibrosis
- 1 in 20 carrier frequency
- heteroyzgote carriers have higher than normal incidence of respiratory and pancreatic disease
Class 1 CF?
defective protein synthesis
Class 2 CF?
abnormal protein folding, processing or trafficking
-includes F508, most common mutation (70% cases)
Class 3 CF?
defective regulation
Class 4 CF?
decreased conductance
Class 5 CF?
reduced abundance of normal protein
Class 6 CF?
altered regulation of other ion channels
Is CF a monogenetic disorder? what other factors play a role?
- yes but there is evidence that other genes can modify the frequency and severity of effects of CFTR mutations on various organ systems
- environmental modifiers can also be very important, various infectious agents, how effectively infections are treated, presence or absence of allergens and pollutants
Effect of enzyme mutation on a metabolic pathway due to recessive inheritance?
one gene in a pathway is affected which leads to accumulation of substrates before it and deficiency of product after it
Examples of autosomal recessive inherited enzyme deficiencies?
- phenylketonuria
- alkaptonuria
- glycogen storage disease
- lysosomal storage disease
Who is more often affected by X linked recessive disorders? why? other characteristics?
- males b/c they are hemizygous for the X chromosome (XY)
- females can only be affected if homozygous (XX), they can be heterozygous carriers
- no father to son transmission
- generations are skipped as it passes through carrier females, more men affected
- affected man passes it to all daughters, half of male grandchildren
Examples of X linked recessive disorders?
- Hemophilia A
- Duchenne muscular dystrophy
What is Hemophilia A? causes? who is affected?
- X linked recessive disorder
- most common inherited disease associated with life threatening bleeding
- caused by mutation in gene encoding Factor VIII
- affects mainly males and homozygous females, very rarely heterozygous females
- 30% have no family history
- wide range of severity
- allelic heterogeneity- many different mutations
What is the role of Factor VIII? what mutations cause hemophilia?
- point mutations usually originate in male germ cells
- deletions occur in female germ cells
What is Duchenne muscular dystrophy? symptoms?
- X linked recessive
- symptoms before age 5
- muscle weakness
- pseudohypertrophy of calves
- wheelchair by age 11
- 25% have IQ lower than 75
- survival beyond age 25 is uncommon
What happens with female heterozygotes of X linked recessive muscular dystrophy?
- usually unaffected
- 8-10% have some degree of muscle weakness
- 2/3 have higher than normal creatine kinase due to breakdown of muscle cells
What is the largest gene known to the human genome? importance?
- DMD gene- 2.3 Mb
- dystrophin Protein is important in maintaining structural integrity of muscle cell cytoskeleton
- high mutation rate
- reproduction is unlikely, almost all cases due to new mutations
What is pseudo hypertrophy of calves due to?
infiltration of fat and connective tissue into the muscle
What happens when muscles die? what is different between a normal person and a person with DMD?
- creatine kinase leaks into serum
- in DMD, serum CK levels are 20X higher than the normal range
- elevated levels can be detected before onset of symptoms
What can other mutations of the dystrophin gene cause?
- Becker muscular dystrophy (BMD)
- X linked recessive
- less sever than DMD
- onset at age 11
- less common
Who is more affected by X linked dominant disorders? transmission?
- females are more affected (2X)
- heterozygous females have milder disease
- no father to son transmission, all daughters affected
Why is the distinction between X linked dominant and X linked recessive blurred?
- incomplete penetrance in heterozygotes for X linked dominant disorders
- occasional presence of disease in heterozygotes for recessive conditions (manifesting hetero)
-less prevalent than recessive
What is Rett syndrome? behavior? causes?
- X linked dominant
- more rare in males because they don’t survive to term
- autistic behavior
- mental disability
- seizures
- gait ataxia
- severity is variable due to lyonization
-most cases are due to mutation of a gene involved in chromatin condensation, causes inappropriate expression of genes involve in brain development (new mutations in paternal germline)
What causes ABO blood type?
- codominance
- presence of A and B antigens on RBCs is determine by a gene with three different alleles (Ia, Ib, i-no A or B)
Codominance?
two allelic traits that are both expressed in the heterozygous state
Type A blood? B? AB? O? How does body recognize?
A-carry A antigen on RBC, anti B antibodies
B- carry B antigen, anti A antibodies
AB- carry both A and B
O- have neither A nor B antigen
- antigens not found on a person’s own RBC will be recognized as foreign by that person’s immune system and antibodies against those antigens are produced
- person with A type given B type in a transfusion will attack the new blood with anti B antibodies
Bombay phenotype?
- has blood type O
- rare recessive (hh) mutation causes failure to make the intermediate (H) that is converted to A or B antigens
- enzyme that converts intermediate into compound H is encoded on H locus
Individuals with blood types A, B, and AB have enzymes that do what?
affect the glycosylation patterns of the basic RBC antigen H. The A and B alleles produce enzymes with different transferase activities that add different sugars
How does the O allele result?
inactive transferase cannot modify antigen H
The enzyme that glycosylates compound H is encoded where?
on the I locus and has allele Ia, Ib, i
