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MutationsMutations
Point mutationPoint mutation– Missense mutationMissense mutation– Nonsense mutationNonsense mutation
Frameshift mutationFrameshift mutation Trinucleotide repeat mutationTrinucleotide repeat mutation
MutationsMutations::
Decreased gene product or inactive protein:Decreased gene product or inactive protein: Enzymes:AREnzymes:AR Regulation of complex metabolic pathways: e.g., LDL receptorRegulation of complex metabolic pathways: e.g., LDL receptor Key structural proteins: dominant negativeKey structural proteins: dominant negative
Gain of function:Gain of function: Almost always AD, e.g., Huntington diseaseAlmost always AD, e.g., Huntington disease
Mendelian DisordersMendelian Disorders
Expressed mutations Expressed mutations in single genes of in single genes of large effectlarge effect
Gene expressionGene expression– DominantDominant– RecessiveRecessive– CodominantCodominant
Pleiotropism vs genetic Pleiotropism vs genetic heterogeneityheterogeneity
Autosomal Dominant DisordersAutosomal Dominant Disorders
Onset: older ageOnset: older age Reduced penetranceReduced penetrance Variable expressivityVariable expressivity New mutation:New mutation:
– Frequency depends on reproductive capabilityFrequency depends on reproductive capability– In egg or spermIn egg or sperm– Germ cells of older fathersGerm cells of older fathers– No increased risk in siblingsNo increased risk in siblings
Examples of AD inheritanceExamples of AD inheritance
Huntington diseaseHuntington disease NeurofibromatosisNeurofibromatosis Tuberous sclerosisTuberous sclerosis Polycystic kidney diseasePolycystic kidney disease Familial polyposis coliFamilial polyposis coli Hereditary spherocytosisHereditary spherocytosis Marfan syndromeMarfan syndrome Familial hypercholestrolemiaFamilial hypercholestrolemia
Autosomal Recessive DisordersAutosomal Recessive Disorders
The largest group in Mendelian disordersThe largest group in Mendelian disorders Almost all of the inborn errors of metabolismAlmost all of the inborn errors of metabolism EnzymesEnzymes Complete penetranceComplete penetrance More uniform expressionMore uniform expression Early onsetEarly onset New mutations: ?New mutations: ?
Examples of AR inheritanceExamples of AR inheritance
Cystic fibrosisCystic fibrosis PKUPKU Lysosomal storage diseaseLysosomal storage disease Sickle cell anemiaSickle cell anemia Congenital adrenal hyperplasiaCongenital adrenal hyperplasia Ehler-Danlos syndromeEhler-Danlos syndrome Spinal muscular atrophySpinal muscular atrophy
X- Linked DisordersX- Linked Disorders
No Y- linked inheritanceNo Y- linked inheritance Almost all recessiveAlmost all recessive Males are hemizygote for X-linked mutant Males are hemizygote for X-linked mutant
genesgenes Random inactivation of one of the X- Random inactivation of one of the X-
chromosomes; chromosomes; partialpartial symptoms,e.g., symptoms,e.g., G6PDG6PD
Examples of XLR inheritanceExamples of XLR inheritance
Duchenne muscular dystrophyDuchenne muscular dystrophy Hemophilia A and BHemophilia A and B G6PD deficiencyG6PD deficiency Wiskott-Aldrich syndromeWiskott-Aldrich syndrome Diabetes insipidusDiabetes insipidus Fragile X syndromeFragile X syndrome
X- Linked DisordersX- Linked Disorders
Rare X-linked DominantRare X-linked Dominant– How is the inheritance?How is the inheritance?– Such as Vitamin D resistant ricketsSuch as Vitamin D resistant rickets
Mendelian DisordersMendelian DisordersBiochemical & Molecular BasisBiochemical & Molecular Basis
Enzyme defectsEnzyme defects Defects receptors & transport systemsDefects receptors & transport systems Alterations in structure, function or quantity Alterations in structure, function or quantity
of nonenzyme proteinsof nonenzyme proteins Genetically determined adverse reaction to Genetically determined adverse reaction to
drugsdrugs
Enzyme DefectsEnzyme Defects
Enzyme:Enzyme:– Quantity.Quantity.– Quality.Quality.
Decreased product.Decreased product.– Albinism.Albinism.
Increased substrate or Increased substrate or intermediates.intermediates.– PKU.PKU.
Ipmaired inactivation of Ipmaired inactivation of toxic substrate.toxic substrate.– Alpha1 Antitrypsin D.Alpha1 Antitrypsin D.
Genetically Determined Adverse Genetically Determined Adverse Reaction to DrugsReaction to Drugs
PharmacogeneticsPharmacogenetics– Enzyme deficiency unmasked by drug Enzyme deficiency unmasked by drug
administrationadministration
G6PD and Primaquine G6PD and Primaquine
Disorders Associated With Disorders Associated With Defects in Structural ProteinDefects in Structural Protein
Fibrillin: Marfan syndromeFibrillin: Marfan syndrome Collagen: Ehler Danlos syndromeCollagen: Ehler Danlos syndrome Dystrophin: Duchene/BeckerDystrophin: Duchene/Becker Spectrin/Ankyrin/Protein 4,1: SpherocytosisSpectrin/Ankyrin/Protein 4,1: Spherocytosis
Marfan SyndromeMarfan Syndrome
Definition: Definition: – Connective tissue (elastic fiber) disorderConnective tissue (elastic fiber) disorder– Major involved organsMajor involved organs
SkeletonSkeleton EyeEye Cardiovascular systemCardiovascular system
Prevalence: 1/10,000 – 1/20,000Prevalence: 1/10,000 – 1/20,000
Marfan SyndromeMarfan Syndrome
Autosomal dominant inheritanceAutosomal dominant inheritance 70-80% familial vs 20-30% new mutations70-80% familial vs 20-30% new mutations Variable expression: genetically heterogeneous Variable expression: genetically heterogeneous MutationMutation
– Almost allAlmost all– Negative dominantNegative dominant– Chromosome 15q21.1Chromosome 15q21.1– FNB1 geneFNB1 gene
Elastic fibersElastic fibers
Central coreCentral core– Predominantly ellastinPredominantly ellastin
Peripheral Peripheral microfibrillary networkmicrofibrillary network– Predominantly Predominantly fibrillinfibrillin
FibrillinFibrillin
Particularly abundant inParticularly abundant in– AortaAorta– LigamentsLigaments– Ciliary zonules of lensCiliary zonules of lens
Marfan SyndromeMarfan Syndrome
PathogenesisPathogenesis– Inherited defect in fibrillin, an extracellular Inherited defect in fibrillin, an extracellular
glycoproteinglycoprotein– FBN1 gene mutationFBN1 gene mutation
70 different mutation70 different mutation Mostly nonsense mutationsMostly nonsense mutations
Marfan SyndromeMarfan Syndrome
Skeletal abnormalitiesSkeletal abnormalities– Most strikingMost striking– Usually tallUsually tall– Upper segment/lower segment: lowUpper segment/lower segment: low– Long extremitiesLong extremities– Pectus excavatumPectus excavatum– Long tapering fingers and toesLong tapering fingers and toes
Marfan SyndromeMarfan Syndrome…Skeletal Abnormalities…Skeletal Abnormalities
Hyperflexibility of jointsHyperflexibility of joints ScoliosisScoliosis KyphosisKyphosis Rotation or slipping of thoracic vertebraeRotation or slipping of thoracic vertebrae Dolichocephalic (long-headed)Dolichocephalic (long-headed)
– Cranial index less than 75%Cranial index less than 75%– Cranial endex: width of skull/length of skullCranial endex: width of skull/length of skull
Bossing of frontal & supraorbital ridgesBossing of frontal & supraorbital ridges
Marfan SyndromeMarfan SyndromeOcular ChangesOcular Changes
CharacteristicCharacteristic– Very rare in those without this diseaseVery rare in those without this disease
Bilateral subluxation or dislocation of lensBilateral subluxation or dislocation of lens– Ectopia lentisEctopia lentis
Marfan SyndromeMarfan SyndromeCardiovascular ChangesCardiovascular Changes
Aortic neurysmAortic neurysm– Cystic medionecrosisCystic medionecrosis
Intimal tearIntimal tear– DissectionDissection
Towards root of aorta or iliacTowards root of aorta or iliac Ruptured dissection: cause of 30-45% of deathsRuptured dissection: cause of 30-45% of deaths
– Aortic regurgitationAortic regurgitation
Marfan SyndromeMarfan Syndrome...Cardiovascular Changes...Cardiovascular Changes
Mitral prolapseMitral prolapse– Loss of connective tissue supportLoss of connective tissue support– More commonMore common– Less seriousLess serious– Floppy valveFloppy valve– Elongated chordae tendineaeElongated chordae tendineae– Similar changes in tricuspid and rarely aortaSimilar changes in tricuspid and rarely aorta
Marfan SyndromeMarfan Syndrome
DiagnosisDiagnosis– Presymptomatic Dx:Presymptomatic Dx:
RFLPRFLP 70 different mutations70 different mutations
– Direct gene diagnosis impossibleDirect gene diagnosis impossible
Defects in Collagen Synthesis or Defects in Collagen Synthesis or StructureStructure
Osteogenesis imperfectaOsteogenesis imperfecta Alport syndromeAlport syndrome Epidermolysis bullosaEpidermolysis bullosa Ehler Danlos syndrome (EDS)Ehler Danlos syndrome (EDS)
CollagenCollagen
Most abundant protein in animal worldMost abundant protein in animal world At least 14 distinct collagen typesAt least 14 distinct collagen types General formulaGeneral formula
– (gly-x-y)(gly-x-y)nn
– Triple helixTriple helix Three Three chains: about 30 chains: about 30 chains chains
Ehler Danlos Syndrome (EDS)Ehler Danlos Syndrome (EDS)
Genetically heterogeneousGenetically heterogeneous At least 10 variantAt least 10 variant Clinical manifestationsClinical manifestations
– SkinSkin HyperextensibleHyperextensible Extremely fragileExtremely fragile
– JointsJoints Prone to dislocationProne to dislocation Hypermobile Hypermobile
Ehler Danlos Syndrome (EDS)Ehler Danlos Syndrome (EDS)
Type VIType VI– Most commom AR form of EDSMost commom AR form of EDS– Mutation in lysyl hydroxylase geneMutation in lysyl hydroxylase gene
Only collagen I and IIIOnly collagen I and III
– Ocular fragility with rupture of cornea and retinal Ocular fragility with rupture of cornea and retinal detachmentdetachment
Ehler Danlos Syndrome (EDS)Ehler Danlos Syndrome (EDS)
Type IVType IV– AD inheritanceAD inheritance– Collagen type IIICollagen type III– At least 3 different mutation:At least 3 different mutation:
Abnormal collagenAbnormal collagen Decreased synthesisDecreased synthesis Decreased excretionDecreased excretion
– Some negative dominantSome negative dominant– Rupture of colon and large arteriesRupture of colon and large arteries
Ehler Danlos Syndrome (EDS)Ehler Danlos Syndrome (EDS)
Type VIIType VII– AD inheritanceAD inheritance– Abnormal procollagen type IAbnormal procollagen type I– Peptidase can not cleave the N terminalPeptidase can not cleave the N terminal– GenesGenes
1[I]1[I] 2[I]2[I]
Ehler Danlos Syndrome (EDS)Ehler Danlos Syndrome (EDS)
Type IXType IX– XLR inheritanceXLR inheritance– Mutation in copper binding proteinMutation in copper binding protein
Decreased activity of lysyl hydroxylaseDecreased activity of lysyl hydroxylase– Cross-linking of collagen & elasticCross-linking of collagen & elastic
– High level of copper within the cellHigh level of copper within the cell– Low serum copper & ceruloplasmin levelsLow serum copper & ceruloplasmin levels
Familial HypercholestrolemiaFamilial Hypercholestrolemia
A receptor diseaseA receptor disease The most frequent mendelial disorderThe most frequent mendelial disorder
– 3-6% of survivors of MI3-6% of survivors of MI
Mutation in the gene encoding LDL receptorMutation in the gene encoding LDL receptor– HypercholestrolemiaHypercholestrolemia
Premature atherosclerosis: MIPremature atherosclerosis: MI XanthomaXanthoma
Familial HypercholestrolemiaFamilial Hypercholestrolemia
HeterozygotesHeterozygotes– 1/5001/500– 2-3 times higher plasma cholestrol2-3 times higher plasma cholestrol
HomozygotesHomozygotes– 5-6 times higher plasma cholestrol5-6 times higher plasma cholestrol– MI before 20 years of ageMI before 20 years of age
Familial HypercholestrolemiaFamilial Hypercholestrolemia
PathogenesisPathogenesis– Decreased LDL clearance (uptake)Decreased LDL clearance (uptake)– Increased LDL productionIncreased LDL production
More IDL coverts to LDLMore IDL coverts to LDL In both heterozygotes and homozygotesIn both heterozygotes and homozygotes
– Increased LDL uptake by Increased LDL uptake by macrophage/monocyte (scavenger receptor)macrophage/monocyte (scavenger receptor) Acetylated or oxidized LDLAcetylated or oxidized LDL
Familial HypercholestrolemiaFamilial Hypercholestrolemia
LDL receptor geneLDL receptor gene– Extremely largeExtremely large
18 exons18 exons 5 domains5 domains 45 kb45 kb
Familial HypercholestrolemiaFamilial Hypercholestrolemia
LDL receptor geneLDL receptor gene– More than 150 different mutationsMore than 150 different mutations
InsertionInsertion DeletionDeletion MissenseMissense NonsenseNonsense
– Mutations categorized in 5 groupsMutations categorized in 5 groups
ManagementManagement
StatinsStatins– HMG-CoA reductase inhibitionHMG-CoA reductase inhibition
Decreased synthesis of cholestrolDecreased synthesis of cholestrol Increased synthesis of LDL receptorIncreased synthesis of LDL receptor
Gene therapyGene therapy
Lysosomal Storage DiseasesLysosomal Storage Diseases
DefinitionDefinition– Lack of any protein essential for the normal Lack of any protein essential for the normal
function of lysosomesfunction of lysosomes
Lysosomal Storage DiseasesLysosomal Storage Diseases
Involved organs depend onInvolved organs depend on– The site where most of the material to be The site where most of the material to be
degraded is found.degraded is found. GM1 & GM2 gangliosidosesGM1 & GM2 gangliosidoses
– BrainBrain MucopolysaccharidosesMucopolysaccharidoses
– All of the bodyAll of the body
– The location where most of the degradation The location where most of the degradation normally occursnormally occurs Mononuclear phagocytesMononuclear phagocytes
Tay-Sachs DiseaseTay-Sachs Disease
Most common form of GM2 gangliosidosesMost common form of GM2 gangliosidoses Ashkenazi jewsAshkenazi jews
– 1/30 carrier rate1/30 carrier rate
All tissues lack hexosaminidase AAll tissues lack hexosaminidase A– Including leukocytes and plasmaIncluding leukocytes and plasma
GM2 accumulation in many organsGM2 accumulation in many organs– Heart, liver, spleen,Heart, liver, spleen,CNS, autonomous nervous CNS, autonomous nervous
system, retinasystem, retina, .., ..
Niemann-Pick DiseaseNiemann-Pick Disease
Rare lysosomal storage diseaseRare lysosomal storage disease Lysosomal accumulation of sphingomyelinLysosomal accumulation of sphingomyelin
– Sphingomyelinase deficiencySphingomyelinase deficiency
Common in Ashkenazi jewsCommon in Ashkenazi jews Types A & BTypes A & B Previously type CPreviously type C
– Defect in intracellular cholestrol esterification & transportDefect in intracellular cholestrol esterification & transport
Niemann-Pick DiseaseNiemann-Pick Disease
Type AType A– Severe infantile typeSevere infantile type
Extensive neurologic involvementExtensive neurologic involvement Severe visceral accumulation of sphingomyelinSevere visceral accumulation of sphingomyelin
– 75-80% of cases75-80% of cases– Survival: less than 3 yearsSurvival: less than 3 years
Niemann-Pick DiseaseNiemann-Pick Disease
……Type AType A Missense mutationMissense mutation Complete deficiency of sphingomyelinaseComplete deficiency of sphingomyelinase
Niemann-Pick DiseaseNiemann-Pick Disease
Type BType B– OrganomegalyOrganomegaly– No CNS involvementNo CNS involvement– Survive adulthoodSurvive adulthood
Niemann-Pick DiseaseNiemann-Pick DiseaseDiagnosisDiagnosis
Biochemical studiesBiochemical studies– Sphingomyelinase activity in leukocytes and Sphingomyelinase activity in leukocytes and
cultured fibroblastscultured fibroblasts
DNA probes:DNA probes:– Both patients and carriersBoth patients and carriers
Gaucher DiseaseGaucher Disease
Glucocerebrosidase gene mutationGlucocerebrosidase gene mutation Accumulation of glucocerebroside in Accumulation of glucocerebroside in
phagocytes and sometimes CNSphagocytes and sometimes CNS
Gaucher DiseaseGaucher Disease
Most common lysosomal storage diseaseMost common lysosomal storage disease TypesTypes
– I (chronic non-neuropathic): 99%I (chronic non-neuropathic): 99% Decreased enzyme activityDecreased enzyme activity Without CNS involvementWithout CNS involvement Predominantly spleen & skeletonPredominantly spleen & skeleton Pancytopenia or thrombocytopenia Pancytopenia or thrombocytopenia Pathologic Fx and bone painPathologic Fx and bone pain Progressive but compatible with long lifeProgressive but compatible with long life European JewsEuropean Jews
Gaucher DiseaseGaucher Disease
……typestypes– II (acute neuropathic)II (acute neuropathic)
No enzyme activityNo enzyme activity No predilection for jewsNo predilection for jews InfantileInfantile Progressive involvement of CNS & early deathProgressive involvement of CNS & early death HepatosplenomegalyHepatosplenomegaly
Gaucher DiseaseGaucher Disease
DiagnosisDiagnosis– HomozygotesHomozygotes
Enzyme activityEnzyme activity– Peripheral blood leukocytesPeripheral blood leukocytes– Cultured skin fibroblastsCultured skin fibroblasts
– HeterozygotesHeterozygotes Enzymatic methods not reliableEnzymatic methods not reliable Detection of mutationDetection of mutation
– More than 30 different mutationsMore than 30 different mutations
Gaucher DiseaseGaucher Disease
ManagementManagement– DifficultDifficult– Replacement therapyReplacement therapy
Recombinant enzyme: extremely expensiveRecombinant enzyme: extremely expensive Bone marrow transplantationBone marrow transplantation Gene therapy: futureGene therapy: future
Glycogen Storage DiseasesGlycogen Storage Diseases
AKA: GlycogenosesAKA: Glycogenoses Genetic disease with metabolic defect in Genetic disease with metabolic defect in
synthesis or catabolism of glycogensynthesis or catabolism of glycogen
Glycogen Storage DiseasesGlycogen Storage Diseases
Hepatic typeHepatic type– HepatomegalyHepatomegaly– HypoglycemiaHypoglycemia– ExamplesExamples
Von Gierke: Glucose-6-phosphatase (I)Von Gierke: Glucose-6-phosphatase (I) Liver phosphorylase (VI)Liver phosphorylase (VI) Debranching enzyme(III)Debranching enzyme(III)
Glycogen Storage DiseasesGlycogen Storage Diseases
Myopathic typeMyopathic type– Muscle weaknessMuscle weakness– Cramps following exerciseCramps following exercise– Following exercise lactate does not increaseFollowing exercise lactate does not increase– ExamplesExamples
McArdle: muscle phosphorylase(V)McArdle: muscle phosphorylase(V) Muscle phosphofructokinase (VII)Muscle phosphofructokinase (VII)
Glycogen Storage DiseasesGlycogen Storage Diseases
MiscellaneousMiscellaneous– Pompe (acid maltase, Pompe (acid maltase, -glucosidase)-glucosidase)
Lysosomal accumulation of glycogenLysosomal accumulation of glycogen Predominantly heart involvementPredominantly heart involvement Early deathEarly death
Disorders With multifactorial Disorders With multifactorial InheritanceInheritance
Some normal phenotypesSome normal phenotypes– HeightHeight– IntelligenceIntelligence– Eye & hair colorEye & hair color
Normal DistributionNormal DistributionNormal DistributionNormal Distribution
90% Samples90% Samples
95% Samples95% Samples
99% Samples99% Samples
+1.65+1.65x x +2.58+2.58xx
xx__
XX
+1.96+1.96xx
-2.58-2.58xx -1.65-1.65xx
-1.96-1.96xx
Disorders With multifactorial Disorders With multifactorial InheritanceInheritance
Different diseasesDifferent diseases– Cleft lip & palateCleft lip & palate– Congenital heart diseaseCongenital heart disease– Coronary heart diseaseCoronary heart disease– HTNHTN– GoutGout– DMDM– Pyloric stenosisPyloric stenosis
Disorders With multifactorial Disorders With multifactorial InheritanceInheritance
Both environment and two or more mutant Both environment and two or more mutant genes (dosage effect)genes (dosage effect)
Not polygenic inheritanceNot polygenic inheritance Variable expressibilityVariable expressibility Reduced penetranceReduced penetrance First rule out mendelian & chromosomal First rule out mendelian & chromosomal
inheritanceinheritance
Disorders With multifactorial Disorders With multifactorial InheritanceInheritance
Risk of expression: # of mutant genes inheritedRisk of expression: # of mutant genes inherited– Severity of diseaseSeverity of disease– # of diseased individuals# of diseased individuals
The rate of recurrence of the disorder (in range of The rate of recurrence of the disorder (in range of 2-7%) is the same for all first-degree relatives of 2-7%) is the same for all first-degree relatives of affected individualsaffected individuals
Identical twins: concordance 20-40%Identical twins: concordance 20-40% Expression of multifactorial traitExpression of multifactorial trait
– Continuous: heightContinuous: height– Discontinuous: DMDiscontinuous: DM
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