遗传2013molecular disease2013 3-b

1、Principles of Molecular DiseaseTaoZhangDepartmentofMedicalGeneticsHealth Science CenterPekingUniversityGeneThe basic hereditary unit, a DNA sequence required for production of a functional product, usually a protein, but rarely, an untranslated RNA. Gene mutationA change in bases sequence or organiz

2、ation of DNA, usually conferring a deleterious effect.Base substitutionCodon mutationPoint mutationStaticmutationFrame-shift mutationFragment mutationMutationDynamicmutationPoint mutationA change in one or few bases of DNA, includingbasesubstitution, Codon mutation and frame-shift mutation.same sens

3、e mutation(silent)non-sense mutation1. Base substitutionmissense mutationterminator codon mutation2. Codon mutation3. Frame-shift mutationdeletion insertioninversion duplicationfusion geneFragment mutationDynamic mutationUnstable trinucleotide repeat amplification,E.g.Fragile X syndrome(CGG) 200,Hun

4、tingtons Disease(CAG) 35.harmfulnessConsequenceof gene mutationneutralityadvantageThe effect of mutation on protein functionDisease-causing mutation1. loss-of-Function Mutation-thalassemiapku2. Gain-of-Function MutationEnhance one Normal Function of a protein hemoglobin KempseyIncrease production of

5、 a Normal proteintrisomy 213. Novel property Mutationsickle cell disease4. Mutation Associated with Heterochronic orEctopic Gene Expressionr- globingene adultoncogene cancerMolecular diseaseThe diseases is caused by gene mutation which lead to protein variants.Hemoglobins and HemoglobinopathiesWHO:w

6、orlds population5% carriers of genes forclinicallyimportant disorders of hemoglobinHuman Hemoglobins and The Genes Human Hemoglobinstwo chains.141aa （）Four Subunitstwo chains. 146aa （ . ）Each subunits:a globin chain and a heme.HemoglobinGene cluster1. and -like genes clusterGenes5 1213 16p13.1p13.3,

7、2n416pter-p13.3zyzya1a2a1531313299 1001412. and -likegenes cluster5GA311p15.5,2n211p15.5GgAgb5313031 104105146PseudogeneThe genes are similar to the normal gene,butwithout normal gene function.e.g, ,Developmental Expression of Globin geneTranscription modification Translation modification Assembly1.

8、 tissue property2. time property3. amounts (Dosage) balanceRegulation1. Structural variants( Abnormal hemoglobin)800Hemoglobinopathies2. Thalassemias (amounts imbalance )4003. Hereditary persistence of fetal hemoglobinAbnormal hemoglobinSickle cell anemia (OMIM # 603903)Sickle cell hemoglobin (HbS)1

9、949PaulingThe first abnormal hemoglobin to be detectedIt is due to a single nucleotide substitution thatchangesthecodon ofthesixth amino acid ofglobinfromglutamic acid to valine(GAGGTG: Glu 6 val).Sickle cell anemia Clinical featuresHbSHbS :HbAHbS :Homozygotes sickle cell Anemia.Heterozygotes sickle

10、 cell trait inlow oxygen pressure IncidenceAbout 1 in 600 African Americans Geographic distributionMost frequently in equatorial Africa World wideGeographic distributionGeneticsAutosomal recessive (AR), gene location 11P15.5Basic defect gene6GAGGTG mRNA6GAGGUG globin6gluValHbS(26Val)2(2s2 ) Patholog

11、yThe mutation (GAGGTG: Glu6val)in globindecreasesthesolubility ofdeoxygenatedhemoglobinandcauseitto formagelatinous network offibrouspolymers.Thus, erythrocytesbecomefirm anddeform intosickle-shaped cells.Sickle cells are unable to pass through smallarteries and capillaries. These becomecloggedand c

12、ause localoxygen deficiencyinthe tissues.Defective erythrocytes are destroyed (hemolysis). Chronic anemia and its numerous sequelae such as heart failure ,liver damage ,andinfection are the result.normal cellssickle cells 僵硬粘滞性 Prenatal diagnosispossible with DNA techniques. TreatmentMolecular Basis

13、 of Abnormal hemoglobin1.Missense mutation:HbS（6gluval)2.Non-sense mutation :Hb Mckees-Rock(145UAUUAA)Hb constant spring（142UAACAA）3.Termination codon mutation:4.Frame-shift mutation:Hb wayne（138UCC）5.Codon mutation:Hb Gum Hiu(91-95)6.Fusion gene:Hb lepore （）Hb anti-lepore（）ThalassemiaAn Imbalance o

14、f Globin-Chain synthesisThe mutations reduce the synthesis or stabilityofeither the - or - globin chain, to cause- or - thalassemia, respectively.The imbalance in the ratio of : chainthe excess normal chains precipitate in thecelldamaging the membrane and leading to redblood cell destructionanemiaFi

15、rst discovered in person of Mediterranean originWide distribute in the worldMediterranean Middle East Ports of AfricaIndia and AsiaDistribute inthe worldAlpha-Thalassemias gene mutation or deletion,- globin is in relative excess0( 1 ) Thalassemiasgenotype ( )two -gene in same 16 chromosome are delet

16、ion( 2 ) Thalassemiasgenotype ( )one -gene in one 16 chromosome isdeletionDeletions of the Alpha-Globin genes1.Hb Barts / ，4（Hb Barts） hydropsfetalis2.HbH /， T / or CS / , 4 (Hb H)precipitationmoderately severe hemolytic anemia3. Alpha - thalassemia trait / or / mild anemia4. Silent carrier / The mo

17、lecular mechanism of -thalassemia1. Deletion FormsHomologous chromosome mistake pairing andunequalcrossoverMost common form2. Nondeletion Forms-genemutationlessBeta- Thalassemias gene mutation or deletion,- globin is in relative excess0 thalassemia- gene mutation or deletion,no - globin- thalassemia

18、- gene variants,Some - globin1. - thalassemiamajorMost patients withoutnormal - thalassemia alleles.Severe anemianeed for lifelong medicalmanagement.0 / 0、0 / 、0 / 0、 0 / 02. - thalassemiaminorpatients have hypochromic, microcytic redslight anemiablood cell,/ A、0 / Aor 0 / A，Hb A2（22）orHb F（2 2）3. H

19、ereditary persistence offetal hemoglobinhigh levelthe persistence ofr- globingeneexpressionthroughoutadultlife. ,r Hb F（2 2）The Molecular Basis ofBeta-thalassemia1. Nondeletion- gene mutationmostcommon form2. DeletionHomologous mistake paring and unequalcrossoverlessMutation site:1. Coding sequences

20、 in - gene 02. 5- regulation sequences in gene 0 or 3. splice junction sequences in - gene 04. 5-capping sequences in - gene 5. 3- tailing sequences in - gene Master: Gene and Gene mutation Molecular disease Hemoglobinopathies Abnormal hemoglobin,Sickle cell anemia Molecular Basis of Abnormal hemogl

21、obin Thalassemia Alpha-Thalassemias ,Beta-ThalassemiasUnderstand: Consequenceofgene mutation The effect of mutation on protein function Human Hemoglobins and Their Genes The molecular mechanism of-thalassemia The molecular mechanism of-thalassemiaThe Molecular and Biochemical BasisofGenetic Diseases

22、TaoZhangDepartmentofMedicalGeneticsHealth Science CenterPekingUniversityEnzyme defects and DiseasesHereditary enzymopathy(Enzymopathy)The inborn errors of metabolism is caused bygene mutation which lead to enzyme protein variants200+( AR)metabolismE23E3PE12S5S4PS3S2S1GeneG1G2G3 ( mutation)EnzymeEABE

23、BCECD（ defect ）MetabolismABCDerrors of metabolismPathologyThe mechanism of Hereditary enzymopathy.1.Product deficienceAlbinismA B CDTyrosinasePAHPheTyrDopaMelanin2.SubstrateaccumulationGlycogen storagediseaseCABD 3. Middle productaccumulationGalactosemiaC ABD 4. Side product accumulationPhenylketonu

24、ria(PKU)A B CDEF5. Product increaseGoutA B C D6. Loss of normalfeedback inhibitionLesch-nyhansyndromeEABCD Phenylketonuria (PKU)PKU (OMIM # 261600)An important cause of mental retardation, PKU is caused by defective function of thephenylalanine hydroxylase (PAH) gene. Clinical features.Mental

25、 retardation“Mousy” odorin urineSeizure disorderHypopigmentation of skin and hairP K U Incidence1 in 16000 in population GeneticsAutosomal recessive (AR), gene location 12q24 ,13 exons, 12 introns, 90kb, mRNA 2.4kb Basic defectMutation in the gene, phenylalaninehydroxylase, which converts phenylalan

26、ine to tyrosinePhenylketonuria (PKU)ProteinProteinPAHTyrosinasePheTyrDopaMelanin( )Phenylpyruvic acidHypopigmentationof skin and hair Mental retardation()Phenyllactic Phenylaceticacidacid“Mousy” odorin urineBenzophenoneAutosomal recessive (AR) PathologyThe derivatives of Phenylalaninedamage the deve

27、loping brain,to causethe “Mousy” odorin urineand Prenatal diagnosisHypopigmentation of skin and hairPossible with DNA techniques TreatmentDietaryreduction ofphenylalaninePharmacogeneticsThe special area of biochemical geneticsthat deals with the variability in response to drugs that is due to genetic variation.Drug response:absorb,transport,metabolize,reaction,excrete drugs .Require many special proteins and enzymesPolymorphisms for drugresponseidiosyncracy（特应性）Mecha