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Flashcards in Biochemistry Deck (126):
1

Chromatin structure

DNA exists in condensed chromatin form in order to fit into nucleus. 

  • DNA wraps around histones to make nucleosome
  • Histones are rich in lysine and arginine
  • H1 binds to nucleosome and to linker DNA
  • In mitosis: DNA condenses to form chromosomes.
  • DNA and histone synthesis occur during S phase

2

Heterochromatin

Condense, transcriptionally inactive, sterically inaccessible

(HighlyCondensed)

3

Euchromatin

Less condensed, transcriptionally active

Eu= truely "transcribed"

4

DNA methylation

Template strand are methylated in DNA replication

  • allows mismatch repair enzymes to distinguish between old and new strands
  • Methylation at CpG islands represses transcription

5

Histone Methylation

Reversibly represses DNA transcription, but can activate it in some cases

6

Histone acteylation

Relaxes DNA coiling, allowing for transcription

7

Purine

A, G

  • Start with sugar + phosphate (PRPP)
  • add base

8

Pyrimidines

C,U,T

  • Thymine has a methyl
  • Uracil in RNA, Thymine in DNA

Synthesis

  • Make Orotic acid
  • add sugar & phosphate (PRPP)
  • modify base

9

Leflunomide

inhibits dihydroorotate dehydrogenase

(carbamoyl phosphate---> Orotic acid)

10

Mycophenolate

Ribavirin

Inhibit IMP dehydrogenase

(IMP--> GMP)

11

Hydroxyurea

inhibits ribonuclotide reductase

  • UDP--> dUDP

12

6 Mercaptopurine (6MP)

Azathioprine (pro-drug)

inhibits de novo purine synthesis

13

5 Flurouracil (5FU)

Inhibits thymidylate synthase

dUMP--> dTMP

decreases deoxythymidine monophosphate

14

Methotrexate (MTX)

Trimethoprim (TMP)

Pyrimethamine

Inhibits dihydrofolate reductase

THF--> DHF

  • DHF required in dUMP--> dTMP
  • leads to decreased dTMP in humans, bacteria and protozoa

 

15

Adenosine deaminase deficiency

Excess ATP and dATP imbalances nucleotide pool via feedack inhibition of ribonuclotide reductase

  • Prevents DNA synthesis and thus decrease lymphocyte count
  • one of themajor causes of autosomal recessive SCID

16

Lesch-Nyhan Syndrome

Defective purine salage due to absent HGPRT 

  • converts Hypoxanthine to IMP & guanine to GMP
  • results in excess uric acid production
  • x-linked recessive
  • Tx: allopurinol or febuxostat

HGPRT

  • Hyperuricemia
  • Gout
  • Pissed off (aggressive)
  • Retardation (intellectual disability)
  • DysTonia

17

DNA replication

  • Origin of replication
  • Replication fork: where leading and lagging strands are synthesized
  • Helicase: unwinds DNA
  • Single stranded binding proteines: prevents strands from re- annealing
  • DNA topoisomerases: creates a single or souble stranded break in helix to add or remove supercoils ( inhibited by fluoroquinolone)
  • Primase: makes an RNA primer on which DNA polymerase can initiate replication
  • DNA pol III: prokaryotic only ( elongation). Has a 3'--> 5' exonuclease for proofreading
  • DNA pol I: prokaryotic only: decreases RNA primer & replaces it with DNA
  • DNA ligase: catalyzes the formation of phosphodiester bond within a second strand of dsDNA
  • Telomerase: RNA dependent DNA pol that adds DNA to 3' end to avoid loss of genetic material

18

Mutations in DNA

Transition: Purine to purine

Transversion: purine to pyrimidine

  • Silent: substitution codes for some amino acid
  • Missense: substitution results in changed amino acid
  • Nonsense: substitution results in early stop codon
  • Frameship: deletion or insertion of a number of nucleotides not divisible by 3 ( results in truncated, nonfunctional protein)

19

Nucleotide excision repair

specific endonucleases release the oligonucleotide containing damaged base

  • DNA polymerase and ligase fill and reseal the gap
  • repairs bulk helix distorting lesion
  • Defective in xeroderma pigmentosum which prevents repair of pyrimidine dimers because of UV light exposure

20

Base Excision Repair

Base specific glycosylase recognize altered base and creates AP site (apurinic/apyrimidinic)

  • One or more nucleotides are removed by AP endonuclease which cleaves 5' end
  • Lyase cleaves 3' end
  • DNA polymerase B fills in gap
  • DNA ligase seals it
  • important in repair of spontaneous deamination

21

Mismatch repair

Newly synthesized strand is recognized, mismatched nucleotides removed and gap is filled and resealed

  • Defected in HNPCC

22

Nonhomologous end joining

Brings together 2 ends of DNA fragments to repair double stranded breaks

  • NO requirement for homology
  • mutated in ataxia telangiectasia

23

mRNA start codons

AUG

  • Eukaryotes: methionine ( can be removed)
  • Prokaryotes: formylmethionine (f-met)

24

mRNA stop codons

  • UGA
  • UAA
  • UAG

25

Regulation of gene expression:

Promoter

Site where RNA pol and other TR find to DNA upstream of gene locus

  • TATA box
  • CAAT
  • promoter mutation commonly results in dramatic decrease in gene expression

26

Regulation of gene expression:

Enhancer

Stretch of DNA that alters gene expression by binding transcription factors

  • Enhancers and silencers may be located close or far from genes it regulates

27

Regulation of gene expression: 

Silencer

Site where repressors bind

28

RNA polymerase

  • RNA pol I: rRNA
  • RNA pol II: mRNA
  • RNA pol III: tRNA

RNA poly II opens DNA at promoter site

a-amanitin (death mushroom): inhibits RNA pol II-- severe hepatotoxicity

29

RNA processing

Initial RNA transcript is heterogenous nuclear RNA (hnRNA) and is then modified to become mRNA

  • 5' cap
  • poly A tail (AAUAAA= polyadenylation signal)
  • splicing of introns

mRNA is transported out of nucleus into cytosol where it is translated

 

30

Splicing of pre-mRNA

  1. Primary transcript combines with small nuclear ribonucleoproteins (snRNPs) and other proteins to form spliceosome
  2. Loop intermediate is generated
  3. Loop is released to remove intron and join exons

ANtibodies to spliceosomal snRNPS (anti-smith antibodies) are highly specific for SLE

Anti-U1 RNP are highly associated with mixed connective tissue disease

31

Introns

Introns are intervening NON-coding regions

32

Exons

Contain actual genetic information.

Exons are Expressed

  • abnormal splicing variants are implicated in some genetic disorders ( B-thalassemia)

33

tRNA structure

  • Clover-leaf form
  • anti-codon end, 3' aminoacyl end
  • amino acid is bound to 3' end of tRNA
  • CCA= can carry amino acid
  • T-arm: necessary for tRNA ribosome binding
  • D-arm: necessary for tRNA recognition by correct aminoacyl tRNA synthetase

34

tRNA charging

Aminoacyl-tRNA synthetase checks amino acid before and after it binds to tRNA

  • incorrect: hydrolyzed
  • mischarged= reads usual codon but inserts wrong amino acid
  • Aminoacyl-tRNA synthetase adn binding of charged tRNA to the codon are responsible for accuracy of amino acid selection

35

tRNA wobble

Accurate base pairing is required only in the first 2 nucleotide positions of an mRNA codon so codons differing int he 3rd wobble position may code for the same tRNA /amino acid

36

Protein Synthesis:

  • Intiation
  • Elongation
  • Termination

  • Initiation: initiated by GTP hydrolysis.
    • Initiation factors assemble 40s ribosomal subunit with tRNA and are released when 60s unit assemble with the complex
  • Elongation: 
    • amino-acyl tRNA binds to A site
    • rRNA (ribozyme) catalyzes peptide bond formation, transfer polypeptide to amino acid in A site
    • Ribosome advances 3' nucleotides towards  3' end, moving peptidyl RNA to P site (translocation)
  • Termination: stop codons recognized by release factor and completed poly peptide is released

37

Post-translational modifications

  • Trimming: removal of N or C terminal
  • Covalent alterations: phosphorylation, glycosylation, hydroxlation, methylation, etc
  • Chaperone proteins: protein folding

38

Tumor suppressor

p53 and hypophosphorylated Rb

  • inhibit G1  to S progression
  • mutation leads to unrestrained cell division
  • Li Fraumeni syndrome

39

Permanent cells

Remain in G0, rengerate from stem cells

  • Neurons, skeletal and cardiac muscle, RBC

40

Stable cells

Enter G1 from G0 when stimulated 

  • Hepatocytes, lymphocytes

41

Labile cells

Never go to G0 

  • divide rapidly
  • most affected by chemotherapy
  • Bone marrow, gut epithelium, skin, germ cells

42

Rough Endoplasmic Reticulum

site of synthesis of secretory proteins

  • Nissl bodies (RER in neurons): synthesize peptide neurotransmitters for secretion
  • Mucus secreting goblet cells and anti-body secreting plasma cells are rich in RER

43

Smooth Endoplasmic Reticulum

Site of steroid synthesis and detoxification of drugs and poisons

  • Lacks surface ribosomes
  • liver hepatocytes and steroid hormone producing cells of adrenal cortex and gonads are rich in SER

44

Golgi

Distribution center for proteins and lipids from ER

  • Modifies N-oligosaccharides on asparagine
  • Adds O-oligosaccaride on serine and threonine
  • adds Mannos 6 phosphate to proteins (to lysosome)
  • Endosomes: send things to lysosomes for destruction or to Golgi for further use

45

I cell disease

Inclusion cell disease

  • Inherited lysosomal storage disease
  • defect in phosphotransferase
  • failure of golgi to phosphorylate mannose resides on glycoproteins
  • proteins are secreted extracellularly rather than to lysosomes
  • results in coarse facial features, clouded corneas, restricted joint movement, high plasma levels of lysosomal enzymes

46

Signal recognition particle

Cytosolic ribonucleoprotein that traffics proteins from ribosome to RER

  • absent: proteins accumuate in the cytosol

47

Vesicular trafficking proteins

COP I:

  • Golgi to golgi
  • Golgi to ER

COP II

  • Golgi to golgi (anterograde)
  • ER to golgi

Clathrin

  • trans golgi to lysosomes
  • plasma membrane to endosomes (receptor mediated endocytosis)

48

Peroxisome

Membrane enclosed organelle involved in catabolism of very long chain fatty acid, branched chain fatty acid and amino acid

49

Proteosome

Protein complex that degrades damaged or Ubiquinated protens

50

Microtubules

Composed of helical array of polymerized heterodimers of alpha and beta tubulin

  • each dimer has 2 GTp bound
  • incorporated into flageallal, cilia, mitotic spindles
  • involved in axoplasmic transport in neurons

Drugs that act on microtubules

  • Mebendazole
  • Griseofulvin
  • Colchicine
  • Vincristine/Vinblastine
  • Paclitaxel

51

Molecular Motor Proteins

Transport cellular cargo toward opposite ends of microtubule tracks

  • Dynein: retrograde to microtubule ( + to -)
  • Kinesin: anterograde to microtubule ( - to +)

52

Cilia Structure

9 +2 arragement of microtubules

53

Kartagener Syndrome

 

  • Primary ciliary dyskinesis
    • Immotile cilia due to dynein arm defect
    • results in male and female infertility
    • increase risk of ectopic pregnancy
    • can cause bronchiectasis, recurrent sinusitis, situs inversus

54

Intermediate filiament

Immunohistochemical stains

  • Vimentin
  • Desmin
  • cytokeratin
  • GFAP
  • Neurofilament

  • Vimentin: connective tissue
  • Desmin: Muscle
  • cytokeratin: epithelial cells
  • GFAP: neuroGlia
  • Neurofilament: neurons

55

Sodium Potassium pump

located on plasma memebrane with ATP site on cytosolic side

  •  3 NA out 
  • 2 K+ in
  • Oubain inhibits by binding K+ site
  • Cardiac glycosides ( digoxin adn digitoxin) inhibit NaK ATPase which leads to inhibition of Na/Ca exchange ( increase Ca leads to increase contractility)

56

Collagen

  • Type I: Bone, Skin, Tendon, (Osteogenesis imperfecta)
  • Type II: Cartilage, vitreous body, nucleus pulposus
  • Type III: Reticulin: skin, blood vessels, uterus, fetal tissue, granulation tissue
  • Type IV: Basement membrane (Alport syndrome)

57

Collagen synthesis

  1. Synthesis (RER): translation of collagen alpha chain (Gly-X-Y, proline/lysine)
  2. Hydroxylation of specific proline and lysine residues (requires vitamin C)
  3. Glycosylation of pro-alpha-chain hydroxylysine residues). Formation of procollagen (triple helix of alpha chain)
  4. Exocytosis: Exocytosis of procollagen into extracellular space
  5. Proteolytic processing: cleavage of disulfide terminal regions to make tropocollagen
  6. Cross-link: makes collagen fibrils (problems lead to Ehlers-Danlos)

58

Osteogenesis Imperfecta

Genetic bone disorder

(brittle bone disease)

  • Autosomal dominant with decreased production of normal type I collagen
  • multiple fractures with minimal trauma
  • Blue Sclera due to translucency of connective tissue over choroidal veins
  • Hearing loss (abnormal ossicles)
  • Dental imperfections

59

Ehlers-Danlos

Faulty collagen synthesis causing hyperextensible skin, tendency to bleed and hypermobile joints

  • may be associated with joint dislocation, berry and aortic aneurysms, organ rupture
  • Classic type: mutation in Type V collagen
  • Vascular type: mutation in Type III collagen

60

Menkes Disease

connective tissue disease caused by impaired copper absorption and transport

  • Leads to decrease activity of lysyl oxidase
  • results in brittle, kinky hair, growth retardation and hypotonia

61

Elastin

Stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava

  • rich in proline, glycine,
  • broken down by elastase which is normally inhibited by alpha 1 anti-trypsin

62

Marfan syndrome

caused by defect in fibrillin ( glycoprotein that forms a sheath around elastin)

63

PCR

Amplify a desired fragment of DNA

  1. Denaturation: DNA is denatured by heating to generate 2 separate strands
  2. Annealing: premade DNA primers anneal to specific sequence on each strand to be amplified
  3. Elongation: heat stable DNA polymerase replicates the DNA sequence following each primer
  4. agarose gel electrophoresis: used for size separation of PCR products compared to DNA ladder

64

Southern Blot

  1. DNA sample is enzymatically cleaved into smaller pieces
  2. electrophoresed on a gel
  3. transfered to filter
  4. filter is soaked in denaturant and exposed to DNA probe that recognizes its complementary strand
  5. filter exposed to film to visualize DNA

65

Northern blot

similar to Southern blot, but RNA sample is used to study mRNA levels ( gene expression)

66

Western Blot

  1. Protein is separated using gel electrophoresis and transferred to filter
  2. labled antibody is used to bind to relevant protein

 

67

South-western blot

Identifies DNA-binding proteins (transcription factors) using labeled oligonuclotide proteins

68

Microarrays

Thousands of nucleic acid sequences are arranged on grids

  • DNA is hybridized to the chip and scanner detects relative amounts of complementary binding
  • used to profile gene expression
  • able to detect SNP and copy number variations

69

ELISA

Used to detect the presence of either a specific antigen (direct) or specific antibody (indirect) in a patient's peripheral blood

  • Indirect: uses a test antigen to see if a specific antibody is present in pts blood. secondary antibody coupled to a label is used to detect the first antibody
  • Direct: uses a test antibody to see if a specific antigen is present in the patient's blood. secondary antibody coupled to a label used to detect antigen

70

FISH

Fluorescent DNA or RNA probe to specific gene site of interest on chromosome

  • used for specific localizaton of genes and direct visualization of anomalies when deletion is too small to be seen on karyotype

71

Cloning methods

Production of recombinant DNA molecule that is self perpetuating

  • Isolate eukaryotic mRNA of itnerest
  • Expose mRNA to reverse transcriptase to produce cDNA
  • Insert cDNA fragment into bacterial plasmids
  • transform recombinant plasmid into bacteria
  • surviving bacteria on antibiotic medium produce cDNA

72

Cre-lox System

Inducibly manipulate genes at specific developmental point

73

RNA interference (RNAi)

dsRNA synthesized that is complementary to mRNA sequence of interest.

DsRNA promote degradation of target mRNA knocking down gene expression

74

Karyotyping

Process in which metaphase chromosomes are stained, ordered and numbered according to morphology, size, arm length ratio and banding pattern

  • can be preformed on blood, bone marrow, amniotic fluid, placental tissue
  • used to diagnose chromosomal imbalances, autosomal trisomies, sex chromosome disorders

75

Co-dominance

Both alleles contribute to the phenotype of the heterozygote

76

Variable Expressivity

Phenotype varies among individuals with same genotype

77

Incomplete Penetrance

Not all individuals with a mutant genotype show the mutant phenotype

78

Pleiotrophy

One gene contributes to multiple phenotyic effects

79

Anticipation

Increased severity or earlier onset of disease in succeeding generations

80

Loss of heterozygosity

If a pt inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted or mutated before cancer develops

(not true of oncogenes)

81

Dominant negative mutation

Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning

82

Linkage disequilibrium

Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance.

  • Measured in a population not in a family
  • varies in different populations

83

Mosaicism

Presence of geneticlly distinct cell lines in the same individual

  • arises from mitotic errors after fertilization
  • somatic mosaicism: mutation propagate through multiple tissues or orans
  • Gonadal mosaicism: mutation only in egg or sperm cells

84

Locus Heterogeneity

Mutations at different loci can produce similar phenotype

85

Allelic heterogeneity

Different mutations in the same locus produce the same phenotype

86

Heteroplasmy

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease

87

Uniparental disomy

offspring recieves 2 copies of a chromosome from 1 parent and no copies from the other

  • Heterodisomy (heterozygous) indicates a meiosis I error
  • Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes and loss of the other of the original pair

88

Hardy Weinberg population genetics

If a population is in Hardy-Weinberg equilibrium and p and q are different frequencies of separate alleles

P2+2pq+q2= 1

  • p2 is freq. of homozygous for p
  • q2 is freq of homozygous for q
  • 2pq is freq of heterozygosity
  • Frequency of x-linked recessive disease in males is q and in females = q2

Assumptions

  • no mutation occuring at the locus
  • natural selection is not occuring
  • completely random mating
  • no net migration

89

Imprinting

at some loci, only one allele is active

  • other is inactive ( imprinted/inactivated by methylation)
  • with one allele active, deletion of active allele leads to disease
  • Prader willi
  • Angelman syndrome

90

Prader Willi Syndrome

Maternal imprinting

  • Gene from mom is normally silent
  • Paternal gene is deleted/ mutated
  • results in hyperphagia, obesity, intelectual disability, hypogonadism and hypotonia

91

Angelman Syndrome

Paternal imprinting

  • gene from dad is silent
  • Maternal gene is deleted or mutated
  • results in inappropriate laughter ( happy puppet)
  • seizure, ataxia, severe intellectual disability

92

Autosomal dominant

  • often due to defects in structural genes
  • many generations
  • both male and female affected
  • often pleotrophic

93

Autosomal recessive

  • 25% of offspring from 2 carrier affected
  • often due to enzyme deficiencies
  • usually seen in only 1 generation
  • Commonly more severe than dominant disorder
  • increase risk consanguineous families

94

X-linked recessive

  • Sons of heterzygous mothers have a 50% chance of being affected
  • no male to male transmission
  • commonly more severe in males
  • females have to be homozygous to be affected

95

x-linked dominant

  • Transmitted through both parents
  • mothers transmit to 50% of daughters and sons
  • fathers transmit to all daughters but no sons
  • Hypophospahtemic Rickets (vitamin D resistant rickets): inherited disorder resulting in phosphate wasting at proximal tubule

96

Mitochondrial inheritance

  • transmitted only through mother
  • all offspring of affected females may show signs of disease
  • variable expression in a population or within a family due to heteroplasmy
  • Mitochondrial myopathies
    • present with myopathies, lactic acidosis and CNS disease
    • secondary to failure in oxidative phosphorylation
    • muscle biopsy shows "ragged red fibers"

97

Autosomal Dominant Diseases

  • AD polycystic kidney disease (ADPKD)
  • Familial Adenomatous polyposis
  • Familial Hypercholesterolemia
  • Hereditary Hemorrhagic telangiectasia
  • Hereditary Spherocytosis
  • Huntington disease
  • Marfan syndrome
  • MEN
  • Neurofibromatosis type I
  • Neruofibromatosis type 2
  • Tuberous sclerosis
  • von Hippel-lindau disease

98

Autosomal Recessive Diseases

  • Albinism
  • ARPKD
  • cystic fibrosis
  • glycogen storage diseases
  • hemochromatosis
  • kartagener syndrome
  • mucopolysaccharidoses (except Hunter)
  • phenylketouria
  • sicle cell anemia
  • sphingolipidoses ( except: Fabry)
  • thalassemia
  • wilsons disease

99

X-linked Recessive Disorders

  • Bruton agammaglobulinemia
  • Wiskott Aldrich syndrome
  • Fabry disease
  • G6PD deficiency
  • Ocular albinism
  • Lesch-Nyhand syndrome
  • Duchenne and Becker muscular dystrophy
  • Hunter Syndrome
  • Hemophilia A and B
  • Ornithine transcarbamylase deficiency 

(Be Wise, Fool's GOLD Heeds Silly HOpe)

100

Autosomal Trisomies

  • Down Syndrome (trisomy 21)
  • Edward's syndrome (trisomy 18)
  • Patau syndromes ( trisomy 13)

101

autosomal polycystic kidney disease

  • always bilateral
  • massive enlargement of kidneys due to multiple large cysts
  • most due to mutation in PKDI (chromosome 16)
    • 16 letters in polycystic kidney
  • or PKD2 on chromosome 4

102

Familal Adenomatous polyposis

colon becomes covered with adenomatous polyps after puberty

  • Progresses to colon cancer unless colon is resected
  • mutation on chromosome 5 (APC gene)
    • 5 letters in polyp

103

Familial Hypercholesterolemia

Elevated LDL due to defective or absent LDL receptor

  • Leads to severe atherosclerotic disease early in life
    • tendon xanthomas ( typically in achilles tendon)

104

Hereditary Hemorrhagic telangiectasia

Inherited disorder of blood vessels

  • telangiectasia, recurrent epistaxis, skin discoloration, arteriovenous malformations, GI bleeding, hematuria
  • Oscler Weber Rendu syndrome

105

Hereditary Spherocytosis

Spheroid erythrocytes due to spectrin or ankyrin defect

  • Hemolytic anemia
  • increased MCHC
  • Tx: splenectomy

106

Huntington Disease

  • Depression, progressive demetia, choreiform movements, caudate atrophy
  • derease levels of GABA and Ach in brain
  • Gene on Chromosome 4
  • Trinuclotide repeat disorder (CAG)
  • increase repeats--> decrease in age of onset

107

Marfan Syndrome

Fibrillin -1 gene mutation

  • connective tissue disoder affectin skeleton, heart and eyes
  • tall with long extremities, pectus excavatum, hypermobile joints, long tapering fincers and toes
  • Cystic medial necrosis of aorta --> aortic incompetence and dissecting aortic aneurysms
  • floppy mitral valve
  • subluxation of lenses, typically upward and temporally

108

Multiple Endocrine Neoplasias

  • Characterized by familal  tumors of endocrine glands
  • affects pancreas, parathyroid, pituitary, thyroid, adrenal medulla
  • MEN2A and MEN2B are associated with the Ret gene

109

Neurofibromatosis Type I 

Von Recklinghausen disease

  • Neurocutaneous disorder characterized by cafe-au-lait spots and cutaneous neurofibromas
  • Autosomal dominant
  • 100% penetrance, variable expression
  • caused by mutations in NF1 gene on Chromosome 17
    • 17 letters in von Recklinghausen

110

Neurofibromatosis type 2

  • Bilateral acoustic schwannomas, juvenile cataracts, meningiomas and ependymomas
  • NF2 gene on chromosome 22

111

Tuberous Sclerosis

Neurocutanous disorder with multiorgan system involvement

  • characterized by hamartomas
  • incomplete penetrance, variable expression

112

Von hippel-lindau Disease

Characterized by development of numerous tumors, both benign and malignant

  • deletion of VHL gene (tumor suppressor) on chromosome 3
    • VHL= 3

113

Cystic Fibrosis

  • Autosomal recessive
  • Defect in CFTR gene (chromosome 7)
  • commonly a deletion on Phe508
  • CFTR encodes an ATP gate Cl- channel that secretes Cl- in lungs and GI Tract and reabsorbs Cl- in sweat glands
  • Mutations leads to misfolder proteins that is retained in RER and not transported to cell membrane
  • leads to decrease in Cl- secretion and increase in Cl- leads to compensatory increase in Na reabsorption via ENaC
  • increases H20 reabsorption leading to abnormally thick mucus in lungs and GI tract
  • Diagnosis: increase Cl- concentratioon in sweat is diagnostic
  • Presentation
    • contraction alkalosis and hypokalemia
    • ECF water and Na loss with K+/H+ wasting
  • Complication
    • recurrent pulmonary infections, chronic bronchitis, bronchiectasis
    • pancreatic insufficiency, malabsorption, steatorrhea, nasal polyps
    • meconium ileus in newborns
    • infertility in males
    • fat soluble vitamin deficiency
  • Treatment
    • N- acetylcysteine to loosen mucus plugs
    • dornas alfa (DNAse) to clear leukocytic debri

114

Duchenne MD

  • X-linked frameshift mutation
  • truncated dystrophin protein
  • causes accerated muscle breakdown
  • weakness begins in pelvic girdle muscles and progresses superiorly
  • pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle
  • Gower maneuer: patients use upper extremity to help them stand up
  • onset before 5 years
  • Dilated cardiomyopathy common cause of death
  • Loss of dystrophin resuls in myonecrosis, increase CPK and aldolase
  • Western blot and muscle biopsy to confirm diagnosis

115

Becker MD

  • usually x-linked point mutation in dystrophin gene ( no frameshift)
  • less severe than Duchenne
  • onset in adolescence or early adulthood

116

Myotonic type I muscular dystrophy

  • CTG tri-nucleotide repeat expansion in DMPK gene
  • abnormal expression of myotonin protein kinase
  • myotonia, muscle wasting, frontal balding, cateracts, testincular atrophy, arrthythmia

117

Fragile X syndrome

  • X-linked defect affecting the methylation and expression of FMRI gene
  • second most common cause of genetic intellectual disability ( after Downs)
  • Post-puberty macroorchidism ( enlarged testes)
  • long face with large jaw, large everted ears, autism, mitral valve prolapse
  • Trinucleotide repeat (CGG)

118

Trinucleotide repeat expansion disorders

  • Fragile X Syndrome: CGG
  • Friedreich ataxia: GAA
  • Huntington disease: CAG
  • Myotonic dystrophy: CTG

119

Down Syndrome

  • Trisomy 21
  • Intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, gap between 1st 2 toes, duodenal atresia, Hirshsprung disease, concenital heart disease, ostium primum type atrial septal defect, Brushfield spots
  • associated with increase risk of ALL, AML and Alzheimers disease
  • most cases due to meiotic non-disjunction of homologous chromosomes
  • 4% of cases due to Robersonian translocation
  • 1% of cases due to mosaicism 
  • First trimester
    • US increased nuchal translucency & hypoplastic nasal bone
    • serum PAPP-A decreased, free B-hCG is increased
  • Second trimester
    • decreased a-fetoprotein
    • increased B-hCG
    • decreased estradiol
    • increased inhibin A

120

Edwards Syndrome

  • Trisomy 18
  • Severe intellectual disability, rocker bottom feet, micrognathia, low set ears, clenched hands, prominent occiput, congenital heart disease
  • Death usually within 1 year of birth
  • First trimester
    • Decreased PAPP-A and free B-hCG
    • decreased a-fetoprotein
    • decreased B-hCG
    • decreased estradiol
    • normal inhibin A

121

Patau syndrome

  • Trisomy 13
  • Severe intellectual disability
  • rocker bottom feet, micropthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactylyl, congenital heart disease
  • death usually in first year of birth
  • First trimester
    • decrease free B- hCG
    • decreased PAPP-A
    • increased nuchal translucency

122

Robertsonian Translocation

non-reciprocal chromosomal translocation that commonly involves chromosomes 13, 14,15,21, 22

  • occurs when the long arm of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost
  • Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance

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Cri-du-chat syndrome

Congenital microdeletion of short arm of chromosome 5

  • 46, AA or XY, 5p-
  • Microcephaly, moderate to severe intellectual disability, high pitched crying/ mewing, epicanthal folds, cardiac abnormalities (VSD)

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Williams Syndrome

Congenital microdeletion of long arm of chromosome 7

  • deleted region includes elastin gene
  • "elfin" facies, intellectual disability, hypercalcemia (increased sensitivity to vitamin D)
  • well developed verbal skills, extreme friendliness with strangers, cardiocascular problems

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22q11 deletion

  • due to aberrant development of 3rd & 4th branchial pouches
  • Presentation: Catch 22
    • Cleft palate
    • Abnormal facies
    • Thymic aplasia
    • Cardiac defects
    • Hypocalcemia (2* to Parathyroid aplasia)
  • Microdeletion of chromosome 22q11
  • DiGeorge Syndrome: thymic, parathyroid, cardiac defects
  • Velocardiofacial syndrome: palate, facial, cardiac defects

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