Patho Exam 2: Genetics

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15 from father deleted =

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Prader-Willi

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prader willi phenotype

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short stature, obesity and hypogonadism.

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CF =

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chromosome 7
7 is chloride channels

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15 from mother deleted =

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angelman

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angelman phenotype (3)

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seizures, ataxic gait, mental retardation

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Retinoblastoma =

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chrom 13 on long arm

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phenotype retinoblastoma

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tumors, b/c tumor suppressor gene doesn't function

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neurofibromatosis =

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17 on long arm

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elephant man syndrome is chrom

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17, neurofibromatosis

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phenotype of neurofibramatosis

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elephant
Café au lait spots to large neurofibroma hanging off the back.

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DNA polymerase roles:

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- reads the template in a 3-5 direction -continuously adds neucleotides
- proofreads the strand

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leading strand of transcription uses

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5-3 template

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lagging strand of transcription uses

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3-5 template, done in pieces

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read

write

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3-5

5-3

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exon;

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contains codons needed to make proteins

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intron:

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fillers for protection from coding mistakes, are spliced out

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RNA polymerase proceeds down the strand in direction:

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3-5 (reading)

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RNA produced/written in direction

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5-3 (writing)

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transcription is

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DNA to RNA; Result is formation of mRNA.

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RNA polymerase binds to:

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promoter site on DNA.

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actrion of RNA polymerase:

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pulls DNA strands apart, allowing unattached DNA bases to be exposed.

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The sequences of bases in the mRNA is complementary to:

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the template strand of DNA

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uracil replaces: .

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thymines

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after termination sequence read:

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RNA polymerase detaches from the DNA and moves out of nucleus and into cytoplasm.

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Amniocentesis detects:

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neural tube defects
which cause an elevation of alph fetoprotein
linked to diseases caused by mutations of single genes.

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Neural tube defects include:

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anencephaly, spina bifida, encephalocele

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Pyramidines:

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Cytosine and Thymine

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Purines:

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Adenine and Guanine

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when to do amniocentesis :

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16th week

elevated risk for a genetic disease/translocation

women > 35

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Polyploidy:

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euploid w/ more than the diploid number of chomosomes

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Trioploidy:

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Zygote having 3 copies of each chromosome rather than the usual 2.

69 chromosomes total

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Tetraploidy =

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euploid cells w/ 92 chromosomes. Causes miscarriage.

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Aneuploid:

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does not contain a multiple of 23 chromosomes.

includes monosomy and trisomy

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Monosomy-

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the presence of only one copy of a given chromosome in a diploid cell. This is a form of aneuploidy.

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Trisomy:

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Three copies of one chromosome. This is a type of aneuploidy.

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Aneuploidy fo sex chromosomes:

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less serious than in autosomes.

w/Y this is b/c Y carries very little genetic material.

A xygote bearing no X will not survive.

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Nondisjunction:

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reason for aneuploidy: homologous chromosomes or sister chromatids fail to separate normally

produces gametes that have 2 copies of a given chrom and others that have no copies.

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Autosomes:

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first 22 of 23 pairs of chromosomes

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Sex Chromosomes:

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1 of 23 pairs of chromosomes

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Euploid:
-

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cells that have a multiple of normal number of chromosomes

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normal gamete:

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haploid

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- normal somatic:

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diploid

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Disjunction:

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normal separation of chromosomes during cell division

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Somatic Cell Therapy:

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less controversial

insert normal genes into the cells w/ a genetic disorder, localized to specific tissues (bone marrow transplants); used in hemophilia, CF, familial hypercholesterolemia, some CA

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Germ Cell Therapy:

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insert genes into embryos

all cells altered and the descendants of that individual would have altered genetics

not used in humans

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Most genetic engineering is done through technology called:

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recombinant DNA

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Key to genetic engineering:

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Bacterial plasmids


DNA Can be extracted from or inserted into bacteria without seriously disrupting bacterial growth or reproduction.

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Bacterial Plasmids:

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Human DNA is incorporated within the plasmid and they now contain human genes and then re enter bacteria.

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Applications for genetic engineering with bacterial plasmids:

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Human insulin and Interferon, cloning of DNA, human growth hormone

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Gene thereapy:

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normal gene is inserted into a human chromosome to counteract the effects of abnormal or missing genes.

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Partial trisomy:

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extra portion of a chromosome is present in only some cells of the body. consequences of partial trisomies less severe.

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test for genetic abnormalities at 2 mos

4mos

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2 mos chronic villi

4 mos amniocentesis

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Trisomy 21=

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down syndrome.

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Clinical pres of trisomy x:

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No overt physical abnormalities. Sterility, menstrual irregularity, and MR.

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Trisomy x=

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instead of 2 xs these females have 3 xs

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Clincial presentation of Downs:

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1/8000 births.
low IQ from 25-70.
low nasal bridge,
epicanthal folds, protruding tounge
flat, low set ears.
Poor muscle tone
short stature.
Congenital heart defects,
reduced ability to fight respiratory infections,
increased leukemia,
by 40 sx identical to alzheimer’s

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Low IQ, low nasal bridge, epicantal folds, protruding tongue, low set ears, congenital heart defects, short stature:

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Down’s

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Cause of Downs:

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97% nondisjunction

30% translocation.

more in older women because of the age of maternal eggs.

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Clinical presentation of Turner:

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Single x chromosomes.
b/c no Y, appear female. sterile w/ gonadal streaks and no ovaries.
Short stature,
webbing of neck,
widely spaced nipples,
coarction of the aorta,
edema of the feet in newborns,
reduced carrying angle at the elbow
sparse body hair.
Some impairment in spatial and mathematical reasoning and ability.

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Turner’s chromosomally is:

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single x, no y. – has 45 chroms

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Cause of Turner:

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loss of paternal X. ½ have simple monosomy x; ½ have more complex X abnormalities.

Normally very lethal during conception. should miscarry

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Female appearance, steril, short, webbed neck, edema in newborns, gonadal streaks, wide nipples, coarcted aorta, sparse body hair:

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Turner’s

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Gynecomastia and male appearance/sterility, small testes, sparse body hair, high pitched voice, mental impairment:

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Klinefelter

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Klinefelter Syndrome:

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has 47 chroms. Individuals with at least two Xs and a Y. male appearance, taller, usually sterile and female like breasts (gynecomastia), high pitched voice, mental impairment, small testes

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Cause of Klinefelters:

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2/3 of cases caused by NONDISJUNCTION of the x chromosomes in the mother

frequence of the disorder rises with maternal age.

Degree of physical and mental impairment increases with every x.

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Each x you add in Klinefelters:

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increases degree of physical/mental impairment

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Cri du chat syndrome:

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Deletion of short arm of chromosome 5.

Low birth wight

mental retard

micorcephaly.

Heart defects and interesting facial appearance.

PEOPLE AT RISK ARE OLDER WOMEN!!!

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Fragile X Syndrome:

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- second most common cause of mental retardation behind down syndrome
- effects more males although all don’t express it
- 1/3 of females that inherit express it

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Chorionic Villus Sampling:

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10th week gestation, 1.0% loss of fetus, extract small amount of villous tissue directly from chorion, does not require culture

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Cycstic Fibrosis:

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- long arm of chromosome 7 which encodes a protein that forms chloride channels

- pancreas becomes obstructed causing malnutrition

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LBW, mental retardation, microcephaly, heart defects are symtoms of:

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cri du chat

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Deletion of arm of chrom 5 =

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cri du chat

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RNA is synthesized from:

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the DNA template. Results in the formation of messenger RNA. mRNA moves out of the nucleus and into the cytoplasm.

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Transcription:

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DNA → RNA

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Protein transcription factors bind at which side of the transcribed gene:

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5’ end

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RNA polymerase binds to:

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the complex of transcription factors. Working together they open the DNA double helix.

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The RNA polymerase proceeds down one strand moving in the direction of:

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3’-5’.

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Site of protein synthesis is:

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ribosome.

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Translation-

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RNA→ Protein

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When transcription is complete:

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1. transcript is released 2. polymerase is released from the DNA.

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As each nucleotide triphosphate added to the 3’ end of the growing strand

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the two terminal phosphates are removed.

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SYNTHESIS OF RNA=

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5’-3’

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Hemophilia:

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X linked/sex linked. Normally expressed in males

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Huntington:

shows up when in life?

type of inheritence

risk of having it if parent has it?

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Shows up later in life (around 40). Autsomal dominant disease / neurologic age dependent penetrance. individual w/ parent w/ disease has a 50% chance of having it

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Hemophilia is expressed in which gender?

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Males, can be in female if both parents have it

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Autosomal recessive inheritance (2 examples):

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hemophelia, cri du chat sndrome

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Criteria for autosomal recessive:

gender

what is often present?

siblings or parents?

% of offspring of carrier parents who will have it?

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1. males and females are affected in equal proportions
2. consanguinity is often present
3. the disease is seen in siblings but usually not in their parents
4. 1/4 of offspring of carrier parents will be affected

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Sickle cell trait:

Sickle cell disease:

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heterozygous carrier "healthy"

homozygous

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Hemophilia Inheritance:

linked to what chromosome?

seen in what gender?

Never transmitted from x to x

gene always passes from x to x

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- X-linked recessive disorder
- trait seen much more often in males than females
- never transmitted from Father to Son
- can be transmitted through a series of carrier females causing appearance of a “skipped generation”
- gene passed from affected father to ALL his daughters
- common mating type: carrier female and normal male
- carrier female will transmit dx to half her sons ( ½ normal and ½ affected) and half her daughters ( ½ normal and ½ carriers)

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ABO Compatability:
Found on chrom ?

Causes what syndrome? what blood type do you have to have to inherit it?

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- chromosome 9
- Nail-Patella syndrome is an autosomal dominant disease consisting of malformed patellae and nails
- mapped to same gene as ABO
- must have A blood type to inherit

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huntington’s:
age
manifestations

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age-dependent penetrance >40
- neurologic disorder, progressive dementia and increasingly uncontrolled movements of the limbs (chorea)

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Hemophilia:
how inherited
how hemo A occurs
how severe hemo A occurs

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- X-linked with mutation
- base substitution resulting in a single amino acid change produces mild form of Hemophilia A
- base substitution resulting in a “stop” codon produces severe form of Hemophilia A

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Helicase:

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enzyme that splits and unwinds the two DNA strands

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Polymerase I: (4 jobs)

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reads the template
adds nucleotides
gets rid of RNA primers
replaces ribose with deoxyribose

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RNA Primase:

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first bonds in the initiation point of the 3’-5’ parent chain. Primase can attract RNA nucleotides which bind to the DNA nucleotides of the 3-5 strand due to the hydrogen bonds between the bases. RNA nucleotides are the primers for the binding of DNA nucleotides.

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Polymerase III:

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First Polymerase III come through after the primase. Then polymerase I. reads from 3-5, synthesizes from 5-3

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Breast cancer:

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If a women has a first degree relative with breast cancer her risk doubles. Recurence risk increases if the age of onset in the affected relative is early and if the cancer is bilateral.

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Type 2 diabetes:

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• 80-90% of all diabetes cases
• Neither HLA nor autoantibodies are commonly seen
• Patient has insulin resistance or diminished insuline production.
• Recurrence risk is .90 in MZ twin, and 10-15% in sibling.

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Type 1 diabetes:

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• auto immune destruction of insulin producing beta cells in the pancrease. T cell activation and autoantibody production.
• Higher incidence with offspring of diabetic father
• Recurrenc risk: .55 MZ twin, 1-6% sibling rate

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Diabetes causes:

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blindness, heart disease, and kidney failure.

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HTN and inheritence:

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20-40% of blood pressure variants genetic
- 60-80% of blood pressure variants environmental

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Ligase:

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Comes through and connects un connected segments.

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Order of RNA synth:

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primase, poly III, poly I, ligase

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Hypocholesterimia inheritance cycle:

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Autosomal dominant

• 1/500 heterozygous for the FH gene; 1 in 1 million is homozygous for the trait

• Serum cholesterol 300-400 in heterozygote, and 600-1200 in homoygote.

• Cholesterol deposits in arteries and skin: xanthomas

• caused by a reduced number of functioning LDL receptors on cell surfaces causing higher levels of circulating cholesterol

• HMG-CoA: inhibits cellular production of cholesterol as exogenous levels rise within the cell

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HTN is a Risk factor for:

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heart disease stroke and kidney disease. 20-40% of BP is genetic.

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Causes of HTN:

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sodium intake, lack of exercise, stress, obesity, smoking and high fat intake.

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Down syndrome:

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translocation in fusion of long arms of 21 and 14.

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Obesity

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• Body mass index of more than 30
• adopted individuals correlated significantly with their natural parents body weights
• Twin studies= higher concordance in MZ twins than DZ twins.
• Gene that codes leptin is involved
• Up risk of HD, stroke, DM2

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Angiotensin II inactivates:

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bradydinin (vasodilator)

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Angiotensis II activates:

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aldosterone (na retentioned), has direct pressor properties, vasoconstricts and increases blood pressure

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Angiotensin I activates:

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angiotensin II

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breast cancer is linked to chromosomes:

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13(BRCA 2) and 17 (BRCA 1).

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Renin is stimulated when:

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decrease in bp, serum sodium. First Angiotensin I is activated and then Angiotensin II which has direct pressor properties and stimulates release of aldosterone (sodium retention) and inactivates bradykinin(vasodilator)

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BRCAs:

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50-80% lifetime risk of developing breast cancer. BRCA 1 also increase risk of ovarian cancer (20-50%), some rise in prostate/colon CA. BRCA 2 increase risk of ovarian cancer (10-20%) and male br ca.

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MALE RISK OF BREAST CANCER linked to gene:

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BRCA 2 (13)

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BothBRCAs increased risks of:

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breast cancer, ovarian cancer,

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If the expression of the disease in the proband of a gene:

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risk of recurrance is higher

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Silent Mutation:

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substitution of one base for another that effects the one codon but does not effect anything later on

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Inversions:

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Dyslexia when there is an inversion of genetic material. ABCDEFG → ABEDCFG (problems usually occur in offspring)

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Duplication:

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less serious consequences

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Nonsense mutations:

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single base change that changes the codon and replication stops.

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Cri du chat is which type of mutation?

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Deletion

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Deletion:

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When something folds on itself and signals to get rid of a part: broken chrom and loss of DNA

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Insertion:

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Part of chromosome 4 gets inserted onto 20, not recipricol

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Frameshift:

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When something accidentally gets added in or lost and AA triplet coding changes, changing codon and AA sequence

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Translocation:

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When part of chromosome 20 is on chromosome 4, and 4 is on 20.

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When you test cross, you always cross with:

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HOMOZYGOUS RECESSIVE!!!

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Expressivity:

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extent of variation in phenotype associated with particular genotype

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Penetrance:

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percentage of people with genotype that exhibit expected phenotype

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Cholestermia
Process in the cell:

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1. low density receptors are synthesized in the ER of the cell
2. from here they pass thorught the Golgi apparatus to the cell surface where part of the receptor proturudes outside of the cell
3. the circulating LDL particle is bound by the LDL receptor and localized in the cell surface depressions
4. The pit/depression brings the LDL into the cell
5. Once inside the LDL is separated from receptor and taken into a lysosome and is broken down
6. the LDL receptor is recirculated back to the surface
7. Free cholesterol is released form the lysosome for incorporation into the cell membrane or metabolism into bile acids or steroieds
8. as cholesterol levels in the cell rise cellular cholesterol synthesis is reduced by inhibition of HMG-CoA reductase
9. rising cholesterol levels also increase the activity of acyl coenzyme A: an enzyme that modifies cholesterol for storage as cholesterol esters.
10. number of LDL receptors is decreased by lowering the transcription rate of the LDL receptor gene itself. This decreases cholesterol uptake.
11. HYPERCHOLESTERIMIA is from issues with production or function or amount of LDL receptors.

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“unaffected” means

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NOT A CARRIER

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“healthy” means

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could be a carrier, but no phenotype

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Hypercholesterolemia results from issues with:

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production of LDL receptors/not enough LDL receptors…leaves LDL in circulation

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Polymorphism:

Back 134

locus has two or more alleles (human genetics is this way)

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Homozygotes are:

Back 135

"true-breeding”: has pharmaceutical and animal implications.

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Every AA has a __ end and a ___ end

which end of the AA determines what type of AA it is?

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carboxy end and an amino end

it is the R-group side chain that changes what type of AA it is.

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DNA structure:

Back 137

sugar molecules attached to Nucleic Acids (there are 4: A-T C-G), each sugar molecue connected by phosphodeister bond.

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Polymorphism:

Back 138

locus has two or more alleles (human genetics is this way)

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Homozygotes are:

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"true-breeding”: has pharmaceutical and animal implications.

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Every AA has a __ end and a ___ end

which end of the AA determines what type of AA it is?

Back 140

carboxy end and an amino end

it is the R-group side chain that changes what type of AA it is.

Front 141

DNA structure:

Back 141

sugar molecules attached to Nucleic Acids (there are 4: A-T C-G), each sugar molecue connected by phosphodeister bond.

Front 142

Where do you easily cut DNA?

Back 142

A-T combos (2 hands) where there are only double bonds, NOT triple bonds, like C-G (3 hands)

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DNA is made up of three structural things:

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a. Pentose sugar (deoxyribose)
b. Phosphate molecules connecting sugar molecules
c. Four bases: pyrimidines (Cytosine and Thymine) and Purines (Adenine and Guanine)

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DNA backbone made up of

Back 144

sugar + phostphate

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Diff. between Nuclear RNA and mRNA is:

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mRNA has the introns splice out.

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when creating mRNA, each base is added to which end of the growing strand?

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Each base is added to 3’ end of growing strand

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When transcription is complete, 2 things happen:

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1) the transcript is released from the polymerase
2)THEN the polymerase is released from the DNA

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ways of dealing with increased cholesterol levels in a cell:

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1. down hmg-coa, which is rate-limiting step in creating cholesterol
2. up acyl-coa/ACAT, which ups storage of cholesterol
3. down LDL receptor, which lowers cholesterol uptake

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**back one for DNA is

Back 149

dyoxiribose

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backbone for RNA is

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ribose**

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genetic notation of trisomy x

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XXX

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genetic notation of turner

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45,X (NO second sex chrom)

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genetic notation of klinefelter

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47, XXY

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pgs 166-167 READ`

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READ AGAIN

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angiotensin II triggers

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release of aldosterone, and thus sodium retention

also, DIRECTLY PRESSOR properties, and thus release of cathecholemines, and vasoconstriction