Pathology (Genetic diseases1)

  1. What are the features of Disorders related to mutations in single genes with large effects?
    • These mutations cause the disease or predispose to the disease and are typically not present in normal population.
    • Highly penetrant, meaning that the presence of the mutation is associated with the disease in a large proportion of individuals.
    • Follow the classic Mendelian pattern of inheritance.
    • Although informative, these disorders are generally rare unless they are maintained in a population by strong selective forces (e.g., sickle cell anemia in areas where malaria is endemic)
  2. What are the features of Chromosomal disorders?
    Like monogenic disease they are uncommon but associated with high penetrance
  3. What are the features of Complex multigenic disorders?
    • more common
    • interactions between multiple variant (polymorphisms) forms of genes and environmental factors
    • no single susceptibility gene is necessary or sufficient to produce the disease
    • each polymorphism has a small effect and is of low penetrance
    • including atherosclerosis, diabetes mellitus, hypertension, and autoimmune diseases
    • GWAS used for studying them
  4. What is a mutation?
    • A mutation is defined as a permanent change in the DNA.
    • Mutations that affect germ cells are transmitted to the progeny and can give rise to inherited diseases.
    • Mutations that arise in somatic cells understandably do not cause hereditary diseases but are important in the genesis of cancers and some congenital malformations.
  5. What are the importance of Point mutations within coding sequences?
    • alter the meaning of the sequence of the encoded protein (missense mutations
    • If the substituted amino acid causes little change in the function of the protein, the mutation is called a “conservative” missense mutation.
    • A “nonconservative” missense mutation replaces the normal amino acid with a very different one
    • a point mutation may change an amino acid codon to a chain terminator, or stop codon (nonsense mutation). 
  6. What are two examples of missense and nonsense mutation in beta chain of hemoglobin?
    • SCA-->  the nucleotide triplet CTC (or GAG in mRNA), which encodes glutamic acid, is changed to CAC (or GUG in mRNA), which encodes valine. This single amino acid substitution alters the physicochemical properties of hemoglobin, giving rise to sickle cell anemia
    • Beta0 thalassemia-->a point mutation affecting the codon for glutamine (CAG) creates a stop codon (UAG) if U is substituted for C. This change leads to premature termination of β-globin gene translation, and the short peptide that is produced is rapidly degraded
  7. ....................... mutation is the major cause of Tay-Sachs disease in Ashkenazi Jews
    A frameshift
  8. What is the importance of Mutations within noncoding sequences?
    • interfere with binding of transcription factors and thus lead to a marked reduction in or total lack of transcription
    • point mutations within introns may lead to defective splicing of intervening sequences. This, in turn, interferes with normal processing of the initial mRNA transcripts and results in a failure to form mature mRNA
  9. What are the features of Trinucleotide-repeat mutations?
    • almost all affected sequences share the nucleotides G and C
    • are dynamic (i.e., the degree of amplification increases during gametogenesis).
  10. Mutations can interfere at which level?
    • Transcription may be suppressed with gene deletions and point mutations involving promoter sequences.
    • Abnormal mRNA processing may result from mutations affecting introns or splice junctions or both.
    • Translation is affected if a stop codon (chain termination mutation) is created within an exon.
    • Finally, some point mutations may lead to the formation of an abnormal protein without impairing any step in protein synthesis
  11. What is the definition of familial, hereditary and congenital?
    • Hereditary disorders, by definition, are derived from one's parents and are transmitted in the germ line through the generations and therefore are familial.
    • The term congenital simply implies “born with.” Some congenital diseases are not genetic; for example, congenital syphilis.
    • Not all genetic diseases are congenital; individuals with Huntington disease, for example, begin to manifest their condition only after their 20s or 30s
  12. ............................ are good examples of codominant inheritance
    Histocompatibility and blood group antigens
  13. A single mutant gene may lead to many end effects, termed ................
  14. What is genetic heterogeneity?
    mutations at several genetic loci may produce the same trait
  15. True or False: Sickle cell anemia is an example of pleiotropism
  16. True or False: profound childhood deafness is an example of heterogeneity
  17. What are the features of AD inheritance?
    • are manifested in the heterozygous state, so at least one parent of an index case is usually affected;
    • both males and females are affected, and both can transmit the condition.
    • When an affected person marries an unaffected one, every child has one chance in two of having the disease
    • With every autosomal dominant disorder, some proportion of patients do not have affected parents. If a disease markedly reduces reproductive fitness, most cases would be expected to result from new mutations. Many new mutations seem to occur in germ cells of relatively older fathers
    • Clinical features can be modified by variations in penetrance and expressivity
    • In many conditions the age at onset is delayed
  18. The proportion of patients who develop the AD disease as a result of a new mutation is related to the effect of the disease on ..............................
    reproductive capability
  19. If a disease markedly reduces reproductive fitness in AD diseases, most cases would be expected to result from .....................
    new mutations
  20. New mutations in AD disease correlate with........
    older age of father
  21. What is incomplete penetrance?
    Some individuals inherit the mutant gene but are phenotypically normal. This is referred to as incomplete penetrance. Penetrance is expressed in mathematical terms. Thus, 50% penetrance indicates that 50% of those who carry the gene express the trait.
  22. What is variable expressivity?
    In contrast to penetrance, if a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals, the phenomenon is called variable expressivity
  23. What is the mechanism of variable expressivity and penertance?
    effects of other genes or environmental factors that modify the phenotypic expression of the mutant allele.
  24. What are the key features of The biochemical mechanisms of autosomal dominant disorders?
    • Most mutations lead to the reduced production of a gene product or give rise to an inactive protein. The effect of such loss-of-function mutations depends on the nature of the protein affected.
    • If the mutation affects an enzyme protein the heterozygotes are usually normal. Because up to 50% loss of enzyme activity can be compensated for, mutation in genes that encode enzymes do not manifest an autosomal dominant pattern of inheritance
  25. What are the two major categories of proteins that are affected in AD disorders?
    • Those involved in regulation of complex metabolic pathways that are subject to feedback inhibition: Membrane receptors such as the LDL receptor; in familial hypercholesterolemia, a 50% loss of LDL receptors results in a secondary elevation of cholesterol that, in turn, predisposes to atherosclerosis in affected heterozygotes
    • Key structural proteins, such as collagen and cytoskeletal elements of the red cell membrane (e.g., spectrin): when the gene encodes one subunit of a multimeric protein, the product of the mutant allele can interfere with the assembly of a functionally normal multimer. Each of the three collagen chains in the helix must be normal for the assembly and stability of the collagen molecule. In this instance the mutant allele is called dominant negative, because it impairs the function of a normal allele (example OI)
  26. What is dominant negative allele?
    • mutant allele impairs the function of a normal allele
    • Example -->OI
  27. The transmission of disorders produced by gain-of-function mutations is almost always ..................
    AD (like Huntington)
  28. What is an example of a gain of function mutation?
    In this disease the trinucleotide-repeat mutation affecting the Huntington gene  gives rise to an abnormal protein, called huntingtin, that is toxic to neurons, and hence even heterozygotes develop a neurologic deficit
  29. What are the categories associated with AD disorders?
    • The more common loss-of-function mutations affect regulatory proteins and subunits of multimeric proteins, the latter acting through a dominant-negative effect.
    • Gain-of-function mutations are less common; they often endow normal proteins with toxic properties, or more rarely increase a normal activity (e.g., activating mutation in the erythropoetin receptor associated with a pathologic increase in red cell production)
  30. What are disorders with AD inheritance?
    • Nervous: Huntington disease, Neurofibromatosis, Myotonic dystrophy, Tuberous sclerosis
    • Urinary: Polycystic kidney disease
    • Gastrointestinal: Familial polyposis coli
    • Hematopoietic: Hereditary spherocytosis, von Willebrand disease
    • Skeletal: Marfan syndrome, Ehlers-Danlos syndrome (some variants), Osteogenesis imperfecta, Achondroplasia
    • Metabolic: Familial hypercholesterolemia, Acute intermittent porphyria
  31. What are the features of AR diseases?
    • (1) The trait does not usually affect the parents of the affected individual, but siblings may show the disease;
    • (2) siblings have one chance in four of having the trait (i.e., the recurrence risk is 25% for each birth)
    • (3) if the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected individual (proband) is the product of a consanguineous marriage
    • The expression of the defect tends to be more uniform than in autosomal dominant disorders.  
    • Complete penetrance is common.  
    • Onset is frequently early in life.  
    • Although new mutations associated with recessive disorders do occur, they are rarely detected clinically.
    • Since the individual with a new mutation is an asymptomatic heterozygote, several generations may pass before the descendants of such a person mate with other heterozygotes and produce affected offspring.  
    • Many of the mutated genes encode enzymes.
  32. What are some AR disorders?
    • Metabolic: Cystic fibrosis, Phenylketonuria, Galactosemia, Homocystinuria, Lysosomal storage diseases, α1-Antitrypsin deficiency, Wilson disease, Hemochromatosis, Glycogen storage diseases
    • Hematopoietic: Sickle cell anemia, Thalassemias,
    • Endocrine: Congenital adrenal hyperplasia
    • Skeletal: Ehlers-Danlos syndrome (some variants), Alkaptonuria
    • Nervous: Neurogenic muscular atrophies, Friedreich ataxia, Spinal muscular atrophy
  33. All sex-linked disorders are....................................
    X-linked, and almost all are recessive
  34. Why there is no Y linked disorder?
    • Several genes are located in the “male-specific region of Y”; all of these are related to spermatogenesis.
    • Males with mutations affecting the Y-linked genes are usually infertile, and hence there is no Y-linked inheritance
  35. What are the features of XL disorders?
    • the male is said to be hemizygous for X-linked mutant genes, so these disorders are expressed in the male.
    • An affected male does not transmit the disorder to his sons, but all daughters are carriers. Sons of heterozygous women have, of course, one chance in two of receiving the mutant gene.
    • The heterozygous female usually does not express the full phenotypic change because of the paired normal allele. Because of the random inactivation of one of the X chromosomes in the female, however, females have a variable proportion of cells in which the mutant X chromosome is active
  36. How can a female show symptoms of G6PD deficiency?
    In the female, a proportion of the red cells may be derived from marrow cells with inactivation of the normal allele. Such red cells are at the same risk for undergoing hemolysis as are the red cells in the hemizygous male. Thus, the female is not only a carrier of this trait but also is susceptible to drug-induced hemolytic reactions. Because the proportion of defective red cells in heterozygous females depends on the random inactivation of one of the X chromosomes, however, the severity of the hemolytic reaction is almost always less in heterozygous women than in hemizygous men
  37. What are some examples of XL disorders?
    • Musculoskeletal: Duchenne muscular dystrophy
    • Blood: Hemophilia A and B, Chronic granulomatous disease, Glucose-6-phosphate dehydrogenase deficiency
    • Immune: Agammaglobulinemia, Wiskott-Aldrich syndrome
    • Metabolic: Diabetes insipidus, Lesch-Nyhan syndrome
    • Nervous: Fragile-X syndrome
  38. What are the features of XL dominant disorders?
    • These disorders are transmitted by an affected heterozygous female to half her sons and half her daughters and by an affected male parent to all his daughters but none of his sons, if the female parent is unaffected.
    • Vitamin D–resistant rickets
  39. What are the four categories of Mendelian disorders?
    • (1) enzyme defects and their consequences
    • (2) defects in membrane receptors and transport systems
    • (3) alterations in the structure, function, or quantity of nonenzyme proteins
    • (4) mutations resulting in unusual reactions to drugs
  40. What are some examples of splice site mutation with reduced amount?
    • Tay Sachs
    • PKU
  41. What are some examples of missense mutation?
    • Marfan
    • Alpha 1 antitrypsin deficiency
  42. What are the three major consequences of enzyme deficiency?
    • Accumulation of the substrate with or without activation of minor pathways (LSD, galactosemia)
    • decreased amount of end product (albinism)/ or if the end product is the feed back inhibitor deficiency of the end product may permit overproduction of intermediates and their catabolic products (Lesch Nyhan)
    • Failure to inactivate a tissue-damaging substrate ( α1-antitrypsin deficiency)
  43. What are the examples of Defects in Receptors and Transport Systems?
    • Receptor mediated endocytosis-->LDLR
    • Transport protein-->CF
  44. What are some examples of Alterations in Structure, Function, or Quantity of Nonenzyme Proteins?
    • alterations of nonenzyme proteins--> SCA
    • Reduced amount of Hb-->Thalassemia
    • collagen, spectrin, and dystrophin abnormality
  45. What are some examples of Genetically Determined Adverse Reactions to Drugs?
  46. What is the triad of Marfan syndrome?
    • AD
    • changes in the skeleton, eyes, and cardiovascular system
  47. What is the function of fibrillin?
    • Fibrillin is the major component of microfibrils found in the extracellular matrix.
    • These fibrils provide a scaffolding on which tropoelastin is deposited to form elastic fibers.
    • Although microfibrils are widely distributed in the body, they are particularly abundant in the aorta, ligaments, and the ciliary zonules that support the lens
  48. What is the pathophysiology of Marfan syndrome?
    • Fibrillin occurs in two homologous forms, fibrillin-1 and fibrillin-2, encoded by two separate genes, FBN1 and FBN2, mapped on chromosomes 15q21.1 and 5q23.31, respectively.
    • Mutations of FBN1 underlie Marfan syndrome (FBN2 gene --> congenital contractural arachnodactyly).
    • Missense mutations that give rise to abnormal fibrillin-1.
    • Bone overgrowth cannot be attributed to changes in tissue elasticity. 
    • Loss of microfibrils gives rise to abnormal and excessive activation of TGF-β, since normal microfibrils sequester TGF-β and thus control the bioavailability of this cytokine.
    • Excessive TGF-β signaling has deleterious effects on vascular smooth muscle development and the integrity of extracellular matrix. 
  49. What is the genetic of Marfan syndrome?
    • Fibrillin 1 gene on chromosome 15
    • AD
    • missense
  50. What are the skeletal morphologic changes in Marfan syndrome?
    • Unusually tall with exceptionally long extremities and long, tapering fingers and toes.
    • The joint ligaments in the hands and feet are lax; typically the thumb can be hyperextended back to the wrist.
    • dolichocephalic (long-headed) with bossing of the frontal eminences and prominent supraorbital ridges.
    • Kyphosis, scoliosis, or rotation or slipping of the dorsal or lumbar vertebrae.
    • pectus excavatum (deeply depressed sternum) or a pigeon-breast deformity
  51. What is the characteristic eye involvement in Marfan syndrome?
    Bilateral subluxation or dislocation (usually outward and upward) of the lens, referred to as ectopia lentis
  52. What are the two mc cardiac manifestation of Marfan syndrome?
    • MVP
    • dilation of the ascending aorta due to cystic medionecrosis
  53. What is the pathophysiology of aortic root dilatation in Marfan syndrome?
    • cystic medionecrosis
    • Loss of medial support results in progressive dilation of the aortic valve ring and the root of the aorta.
    • Excessive TGF-β signaling in the adventia also probably contributes to aortic dilation. Weakening of the media predisposes to an intimal tear, which may initiate an intramural hematoma that cleaves the layers of the media to produce aortic dissection.
    • After cleaving the aortic layers for considerable distances, sometimes back to the root of the aorta or down to the iliac arteries, the hemorrhage often ruptures through the aortic wall
  54. What is the mc cardiac involvement in Marfan syndrome?
  55. What is the pathophysiology of valvular abnormality in Marfan syndrome?
    • Loss of connective tissue support in the mitral valve leaflets makes them soft and billowy, creating the so-called floppy valve
    • Valvular lesions, along with lengthening of the chordae tendineae, frequently give rise to mitral regurgitation.
  56. What is the mcc of death in Marfan syndrome?
    rupture of aortic dissections
  57. What are the signs of Marfan syndrome
    • Thumb sign--> distal phalanx of the thumb protruding beyond the ulnar border of the clenched fist and reflects both longitudinal laxity of the hand and a long thumb
    • Wrist sign--> the first phalanges of the thumb and fifth digit substantially overlap when wrapped around the opposite wrist
    • Pectus carinatum
    • Hindfoot deformity (pes planus)
    • Dural Ectasia
    • Pneumothorax
    • Protrusio acetabuli
    • Reduced upper segment/lower segment ratio (US/LS) AND increased arm span/height
    • Scoliosis or thoracolumbar kyphosis
    • Reduced elbow extension
    • dolichocephaly 
    • MVP
    • Myopia 
    • ectopia lentis,
    • aortic root dilatation involving the sinuses of Valsalva or aortic dissection
  58. What is the cause of Marfan syndrome in those without FBN1 mutation?
    TGFBR mutation
  59. True or False: marfan syndrome is variably expressive
  60. EDSs  occurs due to a defect in..............
    synthesis or structure of fibrillar collagen
  61. What are the genetic disorders associated with abnormal collagen?
    • Epidermolysis bullosa
    • OI
    • EDS
    • Alport
  62. How is the classical EDS inherited?
  63. What are the symptoms of classical EDS?
    Skin and joint hypermobility, atrophic scars, easy bruising
  64. What are the AD types of EDS?
    • Classical (I/II): Skin and joint hypermobility, atrophic scars, easy bruising
    • Hypermobility (III): Joint hypermobility, pain, dislocations
    • Vascular (IV): Thin skin, arterial or uterine rupture, bruising, small joint hyperextensibility
    • Arthrochalasia (VIIa, b): Severe joint hypermobility, skin changes (mild), scoliosis, bruising
  65. What are the AR EDS?
    • Kyphoscoliosis (VI): Hypotonia, joint laxity, congenital scoliosis, ocular fragility
    • Dermatosparaxsis (VIIc): Severe skin fragility, cutis laxa, bruising
  66. What are the symptoms of EDS?
    • abnormal collagen fibers lack adequate tensile strength, skin is hyperextensible, and the joints are hypermobile
    • bending the thumb backward to touch the forearm and bending the knee forward to create almost a right angle
    • Predisposition to joint dislocation
    • The skin is extraordinarily stretchable, extremely fragile, and vulnerable to trauma.
    • Minor injuries produce gaping defects, and surgical repair or intervention is accomplished with great difficulty because of the lack of normal tensile strength
    • Rupture of the colon and large arteries (vascular EDS), ocular fragility with rupture of cornea and retinal detachment (kyphoscoliosis EDS), and diaphragmatic hernia (classical EDS).
  67. What are some internal complications in EDS?
    • Rupture of the colon and large arteries (vascular EDS)
    • ocular fragility with rupture of cornea and retinal detachment (kyphoscoliosis EDS)
    • diaphragmatic hernia (classical EDS).
  68. What are the features of kyphoscoliosis type of EDS?
    • most common AR 
    • mutations in the gene encoding lysyl hydroxylase, an enzyme necessary for hydroxylation of lysine residues during collagen synthesis.
    • Markedly reduced levels of this enzyme.
    • Because hydroxylysine is essential for the cross-linking of collagen fibers, a deficiency of lysyl hydroxylase results in the synthesis of collagen that lacks normal structural stability
  69. vascular type of EDS results from abnormalities of ..........................
    type III collagen
  70. What are the hallmarks of vascular EDS?
    • AD
    • Collagen III(structural)
    • blood vessels and intestines
  71. What is the abnormality in arthrochalasia type and dermatosparaxis type of EDS?
    • Conversion of type I procollagen to collagen.
    • This step in collagen synthesis involves cleavage of noncollagen peptides at the N terminus and C terminus of the procollagen molecule. This is accomplished by N terminal–specific and C terminal–specific peptidases. 
    • In the arthrochalasia structurally abnormal pro α1 (I) or pro α2 (I) chains that resist cleavage of N-terminal peptides are formed. In patients with a single mutant allele, only 50% of the type I collagen chains are abnormal, but because these chains interfere with the formation of normal collagen helices, heterozygotes manifest the disease.
    • By contrast, the related dermatosparaxis type is caused by mutations in the procollagen-N-peptidase genes, essential for the cleavage of collagens. In this case the enzyme deficiency leads to an autosomal recessive form of inheritance
  72. What is the cause of FH?
    • Mutation in the gene encoding the receptor for LDL, which is involved in the transport and metabolism of cholesterol.
    • As a consequence of receptor abnormalities there is a loss of feedback control and elevated levels of cholesterol that induce premature atherosclerosis, leading to a greatly increased risk of myocardial infarction
  73. What are the manifestation of FH?
    • Heterozygotes (1 in 500), have from birth a two-fold to three-fold elevation of plasma cholesterol level, leading to tendinous xanthomas and premature atherosclerosis in adult life.
    • Homozygotes, may have five-fold to six-fold elevations in plasma cholesterol levels. These individuals develop skin xanthomas and coronary, cerebral, and peripheral vascular atherosclerosis at an early age. Myocardial infarction may develop before age 20. 
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  74. the amount of plasma cholesterol is influenced by its synthesis and catabolism, and the ..................plays a crucial role in both these processes
  75. What is the pathway involving cholesterol metabolism outside the liver cells?
    • The first step in this complex sequence is the secretion of VLDL by the liver into the bloodstream. VLDL particles are rich in triglycerides, but they contain lesser amounts of cholesteryl esters.
    • When a VLDL particle reaches the capillaries of adipose tissue or muscle, it is cleaved by LPL, a process that extracts most of the triglycerides.
    • The resulting molecule is IDL which is reduced in triglyceride content and enriched in cholesteryl esters, but it retains two of the three apoproteins (B-100 and E) present in the parent VLDL particle
    • After release from the capillary endothelium, the IDL particles have one of two fates.
    • Approximately 50% of newly formed IDL is rapidly taken up by the liver by receptor-mediated transport. The receptor responsible for the binding of IDL to the liver cell membrane recognizes both apoprotein B-100 and apoprotein E. It is called the LDL receptor. In the liver cells, IDL is recycled to generate VLDL.
    • The IDL particles not taken up by the liver are subjected to further metabolic processing that removes most of the remaining triglycerides and apoprotein E, yielding cholesterol-rich LDL particles. It should be emphasized that IDL is the immediate and major source of plasma LDL.
    • There seem to be two mechanisms for removal of LDL from plasma, one mediated by an LDL receptor and the other by a receptor for oxidized LDL (scavenger receptor)
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  76. What are the two fates of IDL particles?
    • Approximately 50% of newly formed IDL is rapidly taken up by the liver by receptor-mediated transport. The receptor responsible for the binding of IDL to the liver cell membrane recognizes both apoprotein B-100 and apoprotein E. It is called the LDL receptor, however, because it is also involved in the hepatic clearance of LDL, as described later. In the liver cells, IDL is recycled to generate VLDL.
    • The IDL particles not taken up by the liver are subjected to further metabolic processing that removes most of the remaining triglycerides and apoprotein E, yielding cholesterol-rich LDL particles
  77. the immediate and major source of plasma LDL
  78. What are the apoproteins present in IDL?
    apoproteins (B-100 and E)
  79. What are the changes in APO in VLDL, IDL, and LDL?
    • VLDL--> high TG, low CE, APOE,C,B-100
    • IDL--> less TG, more cholesterol, APoE, B100
    • LDL--> no TG, high cholesterol, APOB100
  80. Most plasma LDL is cleared by.......
  81. What are the steps involving in clearing the LDL from plasma by the liver?
    • The first step involves binding of LDL to cell surface receptors, which are clustered in specialized regions of the plasma membrane called coated pits.
    • After binding, the coated pits containing the receptor-bound LDL are internalized by invagination to form coated vesicles, after which they migrate within the cell to fuse with the lysosomes.
    • Here the LDL dissociates from the receptor, which is recycled to the surface.
    • In the lysosomes the LDL molecule is enzymatically degraded; the apoprotein part is hydrolyzed to amino acids, whereas the cholesteryl esters are broken down to free cholesterol.
    • This free cholesterol, in turn, crosses the lysosomal membrane to enter the cytoplasm, where it is used for membrane synthesis and as a regulator of cholesterol homeostasis.
    • The exit of cholesterol from the lysosomes requires the action of two proteins called NPC1 and NPC2 
    • Three separate processes are affected by the released intracellular cholesterol, as follows:  •   Cholesterol suppresses cholesterol synthesis within the cell by inhibiting the activity of the enzyme HMG CoA reductase, which is the rate-limiting enzyme in the synthetic pathway.  •   Cholesterol activates the enzyme acyl-coenzyme A : cholesterol acyltransferase, favoring esterification and storage of excess cholesterol.  •   Cholesterol suppresses the synthesis of LDL receptors, thus protecting the cells from excessive accumulation of cholesterol
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  82. What are the three intracellular processes controlled by cholesterol?
    • Cholesterol suppresses cholesterol synthesis within the cell by inhibiting the activity of the enzyme HMG CoA reductase, which is the rate-limiting enzyme in the synthetic pathway.  
    • Cholesterol activates the enzyme acyl-coenzyme A : cholesterol acyltransferase, favoring esterification and storage of excess cholesterol.  
    • Cholesterol suppresses the synthesis of LDL receptors, thus protecting the cells from excessive accumulation of cholesterol
  83. What is the pathophysiology of FH?
    • In addition to defective LDL clearance, both the homozygotes and heterozygotes have increased synthesis of LDL.
    • The mechanism of increased synthesis that contributes to hypercholesterolemia also results from a lack of LDL receptors
    • IDL, the immediate precursor of plasma LDL, also uses hepatic LDL receptors (apoprotein B-100 and E receptors) for its transport into the liver.
    • In familial hypercholesterolemia, impaired IDL transport into the liver secondarily diverts a greater proportion of plasma IDL into the precursor pool for plasma LDL
  84. What is the mechanism of increased LDL synthesis in FH?
    • IDL, the immediate precursor of plasma LDL, also uses hepatic LDL receptors (apoprotein B-100 and E receptors) for its transport into the liver. 
    • In familial hypercholesterolemia, impaired IDL transport into the liver secondarily diverts a greater proportion of plasma IDL into the precursor pool for plasma LDL
  85. What is the importance of scavenger receptor in FH?
    • The transport of LDL via the scavenger receptor seems to occur at least in part into the cells of the mononuclear phagocyte system.
    • Monocytes and macrophages have receptors for chemically altered (e.g., acetylated or oxidized) LDL.
    • Normally the amount of LDL transported along this scavenger receptor pathway is less than that mediated by the LDL receptor–dependent mechanisms.
    • In the face of hypercholesterolemia, however, there is a marked increase in the scavenger receptor–mediated traffic of LDL cholesterol into the cells of the mononuclear phagocyte system and possibly the vascular walls.
    • This increase is responsible for the appearance of xanthomas and contributes to the pathogenesis of premature atherosclerosis
  86. What is the mechanism of vascular disease and xanthoma in FH?
    In the face of hypercholesterolemia, there is a marked increase in the scavenger receptor–mediated traffic of LDL cholesterol into the cells of the mononuclear phagocyte system and possibly the vascular walls.
  87. What are the five types of FH?
    • Class I mutations are relatively uncommon, and they lead to a complete failure of synthesis of the receptor protein (null allele). 
    • Class II mutations are fairly common; they encode receptor proteins that accumulate in the endoplasmic reticulum because their folding defects make it impossible for them to be transported to the Golgi complex. 
    • Class III mutations affect the LDL-binding domain of the receptor; the encoded proteins reach the cell surface but fail to bind LDL or do so poorly. 
    • Class IV mutations encode proteins that are synthesized and transported to the cell surface efficiently. They bind LDL normally, but they fail to localize in coated pits, and hence the bound LDL is not internalized. 
    • Class V mutations encode proteins that are expressed on the cell surface, can bind LDL, and can be internalized; however, the pH-dependent dissociation of the receptor and the bound LDL fails to occur. Such receptors are trapped in the endosome, where they are degraded, and hence they fail to recycle to the cell surface
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Card Set
Pathology (Genetic diseases1)
Pathology (Genetic diseases1)