Chromosomes & Genetic Dz Flashcards
apportionement of genome over numbers of chromosomes in humans
In humans, 3.2 x 109 nucleotide pairs are distributed over 24 different chromosomes, 46 total
Some species of deer have six and some species of carp have over 100 chromosomes
How to obtain banding patterns of human chromosomes
Giemsa staining
- Picture: Chromosomes are numbered In approximate order of size And were stained during an Early stage of mitosis when*
- The chromosomes are Incompletely compacted*
Why is it hard to cure genetic disease?
don’t know which parts are important (exons) and which are not (introns) – note how little of the chromosome is actually gene.
Regulatory Sequence
part of gene that is neither intron nor exon
It decides which genes will be expressed and become protein (regulates downstream)
To which animal are human chromosomes most closely related?
Chimpanzee
- Human/chimpanzee DNA sequence divergence is only 1.2%
- Human/orangutan sequence divergence is 3%
- Human/human sequence divergence is 0.1%, that is there are 3.2 X 106 differences between you and me
Different states of chromosomes
Chromosomes exist in different states at different times during the cell cycle
Chromosomes are condensed during mitosis
Three chromosome sequences required for cell viability
- Replication Origin is the specific place where DNA synthesis begins; mammalian chromosomes have multiple replication origins (helicase goes to RO)
- Centromere is the attachment site between the chromosome and the mitotic spindle which allows one copy of each of the duplicated chromosomes to go to each daughter cell
- Telomeres are the ends of chromosomes and contain repeated sequences enabling the ends to be efficiently replicated
Importance of segretation in chromosomal replication
attachment, separation, and equal distribution very important – otherwise you end up with deletions, duplications (e.g., monosomy, trisomy)
aneuploid cell: definition
A somatic cell that does not contain a multiple of 23 chromosomes
Trisomy: definition
an aneuploid cell containing three copies of one chromosome
Monosomy: definition
the presence of only one copy of any chromosome
Monosomy vs trisomy prognosis
often lethal, but infants can survive with trisomy of certain chromosomes “It is better to have extra than less”
Trisomies: which allow survival?
13, 18, 21
Can occur for any chromosome at conception, but these are the only forms seen w/frequency
(trisomy 16 is most common among abortuses but not seen in live births)
Why is aneuploidy of sex chromosomes typically less serious that that of the autosomes?
For Y chromosome: very little genetic material For X chromosome: inactivation of extra chromosomes largely diminishes their effect
*a zygote bearing NO X chromosome will not survive
Nondisjunction
- usually cause of aneuploidy
- Failure of homologous chromosomes or sister chromatids to separate normally during meiosis or mitosis
- nondisjunction during either stage of meiosis produces some gametes that have 2 copies of a given chromosome and others that have no copies. When these gametes unite with normal haploid gametes, resulting zygote is monosomic or trisomic for that chromosome
Disjunction
Normal separation of chromosomes during cell division
Homologous chromosomes, sister chromatids
Partial trisomy
Only an extra portion of a chromosome is present in each cell
Chromosomal mosaics: definition, how and where does it happen?
- Possible for trisomies to occur in only some cells of the body
- body has 2 or more different cell lines, each of which has a different karyotype
- Usually formed by early mitotic nondisjunction occurring in one embryonic cell but not in others
Trisomy 21, aka…
- Down Syndrome
- Best-known example of aneuploidy
Incidence of trisomy 21
1:800 live births
Characteristics of person w/trisomy 21
Mentally retarded, low nasal bridge, epicanthal folds, protruding tongue, poor muscle tone (hypotonia), short stature, congenital heart defects, dementia
IQ 25 to 70
Trisomy 21: health consequences
Congenital heart defects in 1/3 to 1/2 of live-born children w/down syndrome
- reduced ability to fight respiratory tract infections
- increased susceptibility to leukemia
- By 40yo, nearly always develop alzheimer-like symptoms
- one of genes that can cause alzheimer dz is located on chromosome 21
Trisomy 21: life expectancy
- 3/4 fetuses w/known down syndrome spontaneously aborted or stillborn
- 20% born w/down syndrome die during first 10 years of life
- If survive >10 years, average life expectancy is 60 years
Causes of trisomy 21
- 97%: nondisjunction during formation of one parent’s gametes during embryonic development
- 90% - 95%: in formation of mother’s egg cell, remaining is paternal
- 1% are mosaics
- 3%: translocations
Chromosomal mosaics and trisomy 21
1% of individuals w/down syndrome known to be mosaics
b/c large number of normal cells, effect is attenuated, symptoms sometimes less severe
how does maternal age affect risk for trisomy 21?
- increases greatly with maternal age
- women <30 yo - 1:1000 - 1:2000
- 35+ - begins to rise substantially
- 45+ - 3% to 5%
Why does maternal age affect risk for trisomy 21?
consequence of maternal egg cells: in arrested stage of prophase I from formation in female embryo until shed in ovulation.
= egg cell formed by 45 year old woman is 45yo. Enough time for accumulation of errors leading to nondisjunction
Risk of trisomies and paternal age
No apparent association
Trisomy 13
Patau syndrome
One of the trisomies associated with survival
associated w/CL/P
**extra: **severe intellectual disability and physical abnormalities in many parts of the body. Individuals with trisomy 13 often have heart defects, brain or spinal cord abnormalities, very small or poorly developed eyes (microphthalmia), extra fingers or toes, an opening in the lip (a cleft lip) with or without an opening in the roof of the mouth (a cleft palate), and weak muscle tone (hypotonia). Due to the presence of several life-threatening medical problems, many infants with trisomy 13 die within their first days or weeks of life. Only five percent to 10 percent of children with this condition live past their first year.
Trisomy 18
One of the trisomies associated with survival
Trisomy X
female that has three X chromosomes.
Termed “metafemales”
Symptoms are variable: sterility, menstrual irregularity, and/or mental retardation. No overt physical abnormalities. Symptoms worsen with each additional X
One of the most common sex chromosome aneuploidies (1:1000 newborn females)
Turner syndrome
45X: Females with only one X chromosome
Characteristics
- Absence of ovaries (sterile)
- Short stature (~ 4’7”)
- Webbing of the neck
- Edema
- Underdeveloped breasts; wide nipples
- Have g_onadal streaks_ and susceptible to cancer
- X is usually inherited from mother
- coarctation of aorta
- spontaneous abortion common if carrying child w/Turner S
Klinefelter syndrome
47XXY: Individuals with at least two Xs and one Y chromosome
Caused by nondisjunction
Characteristics
- Male appearance
- Develop female-like breasts
- Small testes
- Sparse body hair
- Long limbs
- higher voice
- low IQ
Some individuals can be XXXY and XXXXY. The abnormalities will increase with each X.
Alterations in chromosome structure
- chromosome breakage
- spontaneous mutations (transversions)
- UV light induced mutation
- Inversions
- Deletions
- Silent mutations
- nonsense mutations
- frameshift mutations
- translocation
- insertion
Chromosome breakage
If a chromosome break does occur, physiological mechanisms will usually repair the break, but the breaks often heal in a way that alters the structure of the chromosome
Agents of chromosome breakage: Ionizing radiation, chemicals, and viruses
e.g., deletions, duplications, inversions, translocations
Example of deletion
Cri du chat syndrome
“Cry of the cat”
Deletion of short arm of chromosome 5
Low birth weight, metal retardation, and microcephaly
Spontaneous Mutations: Transversions
e. g. cytosine becomes uracil after amine group is lost
(internet: pyrimidine for purine or vice versa)
UV Light Induced Mutation
UV light causes a bulge that changes a single point (this is the phenomenon, could cause any number of mutation types
Inversions
- Two breaks on a chromosome
- Reversal of the gene order
- Usually occurs from a breakage that gets reversed during reattachment
- ABCDEFG may become ABEDCFG
- “balanced” alteration - often no apparent physical affect. Serious problems usuall occur in offspring. Chromosome needs to form a loop to line up w/normal homolog - can lead to duplications/deletions in daughter cells
Deletion
section of dna is deleted
Best example: cri du chat
Duplication
- Presence of a repeated gene or gene sequence
- Rare occurrence
- often associated w/mental retardation
- Less serious consequences because better to have more genetic material than less (deletion)
- Duplication in the same region as cri du chat causes mental retardation but no physical abnormalities (as opposed to deletions -> cri du chat)
- Examples: fragile X, huntington’s
Silent Mutation
code is altered, but expression is not b/c read same amino acid
Nonsense Mutation
Changes to a stop
Where you develop deficiencies
Frameshift Mutation
Alters all ensuing sequences – whole new set of AAs.
Example: PTHrp (necessary in pregnancy, bad in cancer)
Missense mutation
Substitute for one base pair - results in new amino acid
Translocation
- The interchanging of material between nonhomologous chromosomes
- occurs when two chromosomes break and the segments are rejoined in an abnormal arrangement
- e.g., piece of chromosome 4 exchanges w/20, changes lengths and codes of both – identified much more quickly than changes in DNA order
- most clinically significant type: Robertsonian
Insertion
area of one chromosome inserted into non homologous chromosome
Fragile sites
- Fragile sites are areas on chromosomes that develop distinctive breaks or gaps when cells are cultured in a folate deficient medium
- Fragility d/t multiple factors
- Most have no apparent relationship to disease (other than fragile X)
Recurrence Risk
The probability that parents of a child with a genetic disease will have yet another child with the same disease
Recurrence risk of an autosomal dominant trait when one parent is affected by an autosomal dominant disease (Aa) and the other is normal,
the occurrence and recurrence risks for each child are one half
Penetrance
The percentage of individuals with a specific genotype who also express the expected phenotype
Incomplete penetrance
Individual who has the gene for a disease but does not express the disease
Retinoblastoma (eye tumor in children) demonstrates incomplete penetrance (90%) - this means 10% of obligate carriers do not have the disease (gene normally encodes tumor suppressor)
obligate carriers
affected parent and affected children, so must carry the allele
Autosomal dominant disorder
- Abnormal allele is dominant, normal allele is recessive, and the genes exist on a pair of autosomes
- Males and females are affected in equal proportions
- There is no skipping of generations. If an individual has it, one parent MUST also have it. If neither of the parent has the trait, none of the children have it.
- Affected heterozygous individuals transmit the trait to ½ of their children.
Autosomal dominant trait pedigree
pictured: achondroplasia
Expressivity
- variation in a phenotype associated with a particular genotype
- if variable, penetrance may be complete, but severity varies greatly
- This can be caused by modifier genes
Example of complete penetrance, variable expressivity
von Recklinghausen disease/type 1 neurofibromatosis
- gene normally encodes a tumor suppressor
Autosomal dominant
Long arm of chromosome #17
Disease varies from dark spots on the skin to malignant neurofibromas, scoliosis, gliomas, neuromas, etc.
Threshold liability – males vs females and heightened risk
What causes variation in expressivity?
& Example
Several factors possible:
- genes at other loci can sometimes modify the expression (modifier genes);
- environmental factors;
- different types of mutations at the locus w/variation in severity
- e.g. base substitution resulting in single amino acid change usually produces mild form of hemophilia A
- Base substitution resulting in stop codon usually produces a more severe form of hemophilia A
Autosomal recessive disorder
- Abnormal allele is recessive and a person must be homozygous for the abnormal trait to express the disease
- Males and females are affected in equal proportions (on autosomes)
- Carriers (Aa) phenotypically normal
- The disease is seen in children but usually not in their parents.
- On the average, ¼ of the offspring of carrier parents will be affected.
Recurrence risk of an autosomal recessive trait
When two parents are carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25%
Autosomal recessive pedigree
Consanguinity
Mating of two related individuals
Dramatically increases the recurrence risk of recessive disorders
Where are most sex-linked traits located?
Who usually expresses X-linked disorders?
males because females have another X chromosome to mask the abnormal gene
X-linked recessive
- Most X-linked disorders are recessive
- Affected males cannot transmit the genes to sons, but they can to all daughters
- Sons of female carriers have a 50% risk of being affected
- Sex-linked (X-linked) disorders are usually expressed by males because females have another X chromosome to mask the abnormal gene
Robertsonian translocation:
chromosomes 14 and 21
alternate: produces either normal chromosome or translocation carrier w/normal phenotype
adjacent: produces unbalanced gametes and results in conceptions w/translocation down syndrome, monosomy 21, trisomy 14, monosomy 14
Amniocentesis: when, what, why, risks
- when: usually about 16 weeks gestation
- what: withdraw small amount of amniotic fluid from uterus.
- **Why: **
- Culture and karyotype the fetal cells to detect chromosome abnormalities
- Use DNA to test for single-gene d/os
- AFP levels: elevated in NTDs (spina bifida, anencephaly)
- Risks: fetal loss (<1/200 above background loss rate), so usually only for 30-35yo or known risk for specific genetic dz
Single gene disorders (examples)
cystic fibrosis, sickle cell disease, Fragile X syndrome, muscular dystrophy, or Huntington disease, PKU.
Chorionic Villus Sampling (CVS): when, what, why, risks
- When: 10-12 weeks gestation
- **What: **extract small amount of villous tissue directly from the chorion (transcervically or through abdomen). Does not require in vitro culturing of cells for chromosome analysis b/c sufficient numbers directly available in extracted tissue
- **Why: **same genetic info as amniocentesis, but can get info earlier if worried about continuing pregnancy/risk factors
- **Risk: **slightly higher fetal loss rate (~1%) than amniocentesis
Preimplantation genetic diagnosis (PGD): when, what, why, risks
Relatively new procedure
- **When: **early embryos (8-12 cells) created by in vitro fertilization
- What: one or two cells removed from embryo (no damage).
- **Why: **cells can be tested for chromosome abnormalities and single gene d/os. If found, embryo not implanted in mother’s uterus
- **Risks: **none
Analysis of fetal DNA in maternal ciruculation: when, what, why, risks
- **When: **by 6-8 weeks gestation, fetals cells in mother’s bloodstream
- **What: **test fetal cells (or cell-free fetal DNA) for some disease causing mutations
- **Why: **early diagnosis, minimal risk to mom & fetus
- Risks: minimal - but still in experimental stage
Other prenatal screening measures
- some use maternal serum to asses risk of trisomy 21, 13, 18, and NTDs
- if positive, diagnostic is amniocentesis
- Newborn screening: for genetic conditions like PKU and galactosemia.
- If positive, diagnostic is DNA sequencing
euploid cells
have multiple of the normal number of chromosomes. Normal gamees are haploid and most normal somatics are diploid - so they’re both euploid
polyploidy
When a euploid cell has more than the diploid number of chromosomes.
Several types of body tissue are normally polyploid: e.g., some liver, bronchial, and epithelial tissues
Triploidy & tetraploidy
**Triploidy: **When a zygote has three copies of each chromosome, rather than the usual 2
**Tetraploidy: **euploid cells have 92 chromosomes (4 copies of each)
Nearly all triploid and tetraploid conceptions are spontaneously aborted or stillborn, and the small portion that survive to term die shortly thereafter. 10% of all known miscarriages.
Fragile X syndrome
- Site on the long arm of the X chromosome
- d/t high number of repeated sequences on first exon of Fragile X gene
- Associated with mental retardation; second in occurrence to Down syndrome
- Higher incidence in males because they have only one X chromosome
- Males 1:4000
- Females: 1:8000
Fragile X: repeated sequences & risk
- Expression of fragile X: (>200) repeated DNA sequences in first exon of fragile X gene
- repeats are CGG sequences duplicated many times.
- Most people have fewer than 50 repeats, but if 50 - 200, more likely to produce affected offspring. Over time, leads to expression of fragile X.
- >20 other genetic dz d/t same mechanism
Retinoblastoma: mode of inheritance, pathophysiology
Autosomal dominant
Incomplete penetrance - 90%; b/c 10% of obligate carriers don’t have the disease
D/t mutation in tumor suppressor gene. Not regulating the cell cycle to stop abnormal division.
Huntington: mode of inheritance, pathophys
- autosomal dominant
- Main features: progressive dementia & increasingly uncontrollable movements of limbs
- age-dependent penetrance: usually starts at 40+ yo, so already have kids.
- kids have 50/50 chance of developing during middle age. Then must ask whether they should have kids.
age dependent penetrance
Starts when older : so already had kids - would not have been able after and dz would no longer exist, but as such lives on
Examples: huntingtons, familial breast cancer, hemochromatosis, polycystic kidney disease
von Recklinghausen Disease: mode of inheritance, pathophys
aka type I neurofibromatosis
autosomal dominant, variably expressive
Patho: neurofibromatosis gene encodes a tumor suppressor. Develops a mutation.
Expression: variable. few harmless cafe au lait spots on skin to malignant tumors, scoliosis, seizures, gliomas, hypertension, learning disabilities, and neuromas
Hemophilia: mode of inheritance, pathophys
X linked recessive
Hemophilia A: base substitution resulting in single AA change –> mild form
Base substitution resulting in “stop” codon (thus premature termination of translation) –> more severe form
Autosomal recessive disorders: examples
- Sickle Cell Disease
- Cystic Fibrosis
- Chromosome 7
- Hemochromatosis
- Tay-Sach’s
Sickle Cell: mode of inheritance, clinical features
- autosomal recessive
-
Symptoms:
- O2 can’t reach spleen, liver, kidneys, lungs, heart, other organs. Without oxygen, the cells that make up these organs die. e.g., the spleen destroyed —> loss of immune function —> frequent infections.
- RBCs have shorter lives —> low red blood cell counts, thus “sickle cell anemia”
- Sickle-shaped red blood cells get stuck in blood vessels —> episodes of pain called crises.
- delayed growth, strokes, and jaundice (yellowish skin and eyes because of liver damage).
- Organ damage and other complications often shorten patients lives by about 30 years.
- Pathophys: Hb molecule has 2 parts, alpha & beta. Mutation in a gene on chromosome 11 that codes for the beta subunit of the hemoglobin protein. As a result, hemoglobin molecules don’t form properly, causing red blood cells to be rigid and have a concave shape (like a sickle used to cut wheat). These irregularly shaped cells get stuck in the blood vessels and are unable to transport oxygen effectively, causing pain and damage to the organs.
Cystic Fibrosis: mode of inheritance, patho, clinical features
- autosomal recessive
- most common lethal disease in white children - 1:2500 births, ~1 in 25 whites carries a copy of the allele
- **patho: **CF gene encodes a protein that forms chloride channels in membranes of specialized epithelial cells. Defective Cl- transport –> salt imbalance –> secretions of abnormally thick, dehydrated mucus
- Symptoms: some of digestive organs, esp pancreas, clogged w/mucus –> susceptible to bacterial infections (esp Pseudomonas). Death from lung dz or HF on avg by 40yo
Hemochromatosis: mode of inheritance, clinical features
autosomal recessive, age dependent penetrance
genetic d/o of iron metabolism and most severe example of iron overload
Tay-Sach’s: mode of inheritance, clinical features
autosomal recessive
- Commmon in Ashkenazi Jewish population
- **Patho: **Lysosomal storage d/o. progressively destroys nerve cells (neurons) in the brain and spinal cord.
- **Symptoms: **
- most common form apparent in infancy. appear normal until the age of 3 to 6 months, when their development slows and muscles used for movement weaken. lose motor skills such as turning over, sitting, and crawling. develop an exaggerated startle reaction to loud noises. Over time, experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Children with this severe infantile form of Tay-Sachs disease usually live only into early childhood.
- Can also appear in later childhood or even adulthood. Usually milder.
Autosomal dominant examples
- Huntington’s
- Chromosome 4
- Neurofibromatosis
- Chromosome 17
- Retinoblastoma
- Chromosome 13
- Familial Hypercholesterolemia
- Breast Cancerà BRCA1/BRCA 2
How is cholesterol taken into the cell?
Endocytosis, in LDLs - taken into cell via LDL receptors on cell’s surface
Familial Hypercholesterolemia: mode of inheritance, clinical presentation, risks, patho
- autosomal dominant
-
Incidence: Common
- Accounts for 5% MIs in <60yo
- 1:500ppl heterozygote.
- 1: 1 million homozygotes –> much more severe
- Clinical presentation: plasma chol levels ~2x normal (300-400mg/dl), xanthomas
-
Risks:
- men: 75% develop CD and 50% have fatal MI by 60yo
- Women: 45% & 15%
- homozygotes: Most MI before 20yo, die before 30 if untreated
- Patho: most often reduction in functional LDL receptors
Pathophysiology of LDL-receptor disfunction
autosomal dominant (leads to familial hypercholesterolemia)
- >1000 mutations (missense, nonsense, insertions, deletions) in LDL receptor gene
- 5 classes based on effect on receptor activity
- result in no detectable protein product
- result in production of LDL receptors, but altered so can’t leave ER, eventually degraded
- produce LDL receptorcapable of migrating to cell surface but not of normal binding to LDL
- Normal except don’t migrate specifically to coated pits and thus can’t carr LDL into cell (rare)
- LDL that can’t dissociate from LDL particle after entry into cell. Receptor can’t return to cell surface & is degraded.
- Aa: 1/2 the normal LDL receptors
- AA: almost no functioning LDL receptors
Therapy for Familial Hypercholesterolemia: Aa
- Dietary reduction of cholesterol (reduced sat fats)
- only a modest effect on Aas
- Administration of bile acid-absorbing resins, e.g. cholestyramine. Absorbed Chol is then excreted.
- chol is reabsorbed in gut then recycled through liver (where most chol synthesis takes place)
- Fun fact: Reduced recirculation from gut causes liver cells to form more LDL receptor, further lowering cirulating CHOL! but* *also stimulates chol synthesis by liver cells, so overall reduction is only 15 to 20%
- 2 is more effective combined w/agents that reduce chol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins)
- decreased synthesis –> further production of LDL receptors!
- Together, 2 & 3 can lead to ~ normal levels
Therapy for Familial Hypercholesterolemia: AA
For homozygotes, not so bright
- Therapies for Aas can increase elimination & reduce synthesis of cholesterol, but AAs have few to no LDL receptors, so ineffective
- Liver transplants: sometimes effective, but limited donors
- Plasma exchange Q1-2weeks, in combo w/drug therapy can reduce chol 50%, but hard to do for long periods
- Somatic gene therapy: hepatocytes carrying normal LDL receptor genes introduced into portal circulation now being tested. Stay tuned.
CHD
- leading killer of Americans: 25% of all deaths in U.S.
- atherosclerosis –> MI or CVA
- Risk factors: obesity, smoking, HTN, elevated chol, family Hx (2-7x more likely)
- Family Hx: risk increases if: more affected relatives, female relatives (less affected sex), age of onset before 55
- Role of genes: looking at role of lipids, esp LDL-receptor defects & familial hypercholesterolemia
- Risk can be greatly reduced by modifying environmental factors! Diet, exercise, smoking…
Hypertension: role of genes & environment
- Key risk factor for heart disease, stroke, kidney diseas
- Role of genes: 20-40% of variation in BP caused by genetic factors.
- Role of environment: Even more than genetic! Na+ intake, physical activity, psychosocial stress, obesity (obesity inc genetic factors)
RAAS & HTN: genetic factors
Linkage & association studies have implicated several genes involved in the rening-angiotensin system (genes that encode angiotensinogen, ACE, type I and angiotensin type II receptor) in causation of HTN
Cancers that cluster strongly in families
breast, colon, prostate, ovarian
Breast Cancer: risk, mode of inheritance, genetic factors
autosomal dominant
- affects 12% of women who live to 85+
- One affected 1st degree relative: risk doubles. Even higher if age was early and cancer bilateral.
- Genes: BRCA1 (chromosome 17) and BRCA 2 (chromosome 13)
- Inherited mutations –> 50 to 80% lifetime risk of BC
- BRCA1: increased risk ovarian cancer (20-50%) & modestly increased risk prostate and colon
- BRCA2: 6% males with mutation will develop BC (100fold increase to gen male pop)
- Other inherited mutated tumor supressor genes cause: CHK2, TP53
BRCA1: risk
50-80% lifetime risk BC
increased risk ovarian cancer (20-50%) & modestly increased risk prostate and colon
BRCA2: risk
50 - 80% lifetime risk BC
6% males with mutation will develop BC (100fold increase to gen male pop)
Can test for BRCA 1 or 2?
Yes. DNA test.
Colorectal Cancer
- 2nd to lung cancer - 1:20 Americans will develop
- Clusters in families
- single gene traits:
- familial adenomatous polyposis. Rare - 1:8000. Gene responsible, APC, is a tumor suppressor.
- somatic mutations of APC found in 85% of colon tumors, so even though familial version is rare, APC is typically involved in any colon cancer
- Hereditary nonpolyposis colorectal cancer: 5% colorectal cancers. Mutation in any of 6 genes, all involved in DNA repair.
- familial adenomatous polyposis. Rare - 1:8000. Gene responsible, APC, is a tumor suppressor.
- Other causes thought to involve interaction of multiple genes.
- Environmental factors: high fat, low fiber diet
DM is the leading cause of…
blindness, heart disease, kidney failure
Type 1 diabetes: patho
- Usually presents before 40yo
- autoimmune:
- Characterized by T cell infiltration of pancreas and destruction of insulin producing beta cells
- autoAbs formed agains pancreatic cells (can be observed long before clinical sx)
- strong association between DMI and several human leukocyte antigen (HLA) class II alleles
- Insulin gene involvement? ~10%
- Several other possible genes: CTLA4 (T cell proliferation), PTPN22 (T cell activation)
DMI: genetic risk
- Siblings of affected: 6% risk (gen pop 0.3% to 0.5%)
- Identical Twins: 30% to 50%
- not 100% so not solely genetic
- good evidence specific viral infections initiate in some (activate immune response)
- Dizygotic twins: 5% to 10%
- Risk if mom diabetic: 1% to 3%
- Risk if dad diabetic: 4% to 6%
- *difference is inconsistent w/threshold model since affects sexes equally
HLA system and DMI
- HLA system: accounts for 40% familial clustering of Type I
- 90% whites w/DMI have HLA DR3 and/or 4. Only 50% of gen pop
- If proband & sibling Aa for DRe and DR4 alleles, sibling’s risk is ~20%
- Aspartic acid at position 57 of DQ chain strongly associated w/resistance
- not have AA, 100x more likely to develop DMI
- AA alters shape of HLA class II molecule and ability to present peptides to T cells –> altered T cell recognition
Human Leukocyte Antigen Class II alleles
DMI and insulin gene
Insulin gene: short arm chromosome 11
inherited genetic variation in insulin region accounts for ~10% of familial clustering
PTPN22
gene that encodes a lymphoid specific tyrosine phosphatase that negatively regulates T cell activation
assoc w/DMI, SLE, RA, autoimmune thyroid dz, etc.
Type 2 Diabetes: strong correlation with which of the following
obesity, HLA, Abs
only obesity
DMII monozygotic twin concordance rates
substantially higher than DMI: >90%
*take into account increased age - older subjects studied
Recurrence Risk DMII
Higher than DMI: 15 to 40%
Genes contributing to DMII
- TCF7L2: varint assoc w/50% increased risk of developing DMII
- also assoc w/allele that encodes PPAR-gamma (peroxisome proliferator-activated receptor gamma) - A TF involved in adipocyte differentiation & glc metabolism
- only 25% increased risk, but in 75% of european descent, so significant
- KCNJ11: K+ channel involved in glc stimulated insulin secretion (20% risk)
Most common risk factors for DMII
- family Hx
- obesity (increased insulin resistance)
- Diet & exercise pattern typical to U.S. & europe
Exercise & DMII
Reduces obesity, increases insulin sensitivity, improves glc tolerance
MODY
- autosomal dominant, DMII
- “MODY”: maturity-onset diabetes of the young
- 1/2 caused by mutations in glucokinase gene.
- glucokinase converts glc to glc-6-phosphate in pancreas
- 5 other genes involved in pancreas dvpt or regulation of insulin levels also causes
- *most DMII is not autosomal dominant
Genetic components to obesity
- Rarely, mutations in leptin gene and receptor r/t severe obesity.
- Leptin hormone is secreted by adipocytes and binds to receptors in hypothalamus (appetite control center)
- Melanocortin-4 receptor (MC4R) also involved in appetite control: mutations in 3% to 5% of severely obese
- Homozygosity in DNA variant in FTO gene (seen in 16% whites) assoc w/40% to 70% increases in risks of overweight & obesity, respectively
Common X linked D/Os
- Duchenne Muscular Dystrophy
- Hemophilia (A & B)
- Colorblindness
Continuum of genetic dz. What is the effect of lifestyle/environment vs Genetics for
CF/hemophilia vs flu/measles vs DM/HD
•Duchenne Muscular Dystrophy: mode of inheritance, clinical presentation, patho
- most common and severe X-linked recessive
- 1:3500 males
- Clinical presentation: progressive muscle degeneration. Usually unable to walk by 10 to 12yo
- Death by respiratory or cardiac failure typically before 20yo
-
Patho: DMD gene - largest gene ever found in human, spanning >2million DNA bases, encodes a previously undiscovered muscle gene called dystrophin
- dystrophin: essential role in maintaining structural integrity of muscle cells. W/o, muscle cell can’t survive
- Most commonly caused by DELETIONS in DMD gene
- frameshift deletion: more severe
- In frame deletion (3 bases deleted) produces milder form: the Becker type
•Colorblindness: mode of inheritance
X linked recessive
mutation hot spots
DNA sequences that have particularly high mutation rates - esp CG sequences
Robertsonian translocation
long arms of 2 nonhomologous chromosomes fuse at centromere (new chromosome from short arm is typically useless). Small number of downs cases d/t this
confined to 13, 14, 15, 21, 22 b/c short arms of these small & basically no genetic material.
So carriers lose no important genetic material, bt offspring may have serious deletions or duplications (e.g., Down)
