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Molecular and Biochemical Basis of genetic Disorder Prof. Dr. Müjgan CENGİZ Principles of molecular disease * Molecular reason of a genetic disease is a mutation. This mutation either inherited or acquired. *The biochemical genetic is study of phenotype at the level of proteins, biochemistry and metabolism. A genetic disease occurs when an alteration in the DNA of an essential gene changes the amount or function or both, of the gene product -mRNA and protein. Single Gene disorders almost always results from mutations that alter the function of a protein. The pathologies because of the defaults of a protein expression can 1-Mutations at the control genes. 2-Mutations at the structural genes. The mutations at the control genes causes single nucleotide change. The amount of the polypeptide and function does not effected. Only the velocity of protein synthesis changes, phenotype is normal. Mutations taking place at the structural genes causes a genetic disease . The amounts and functions of gene products decreases. To uderstand the pathogenesis of a genetic disease we have to learn the knowledge of primary abnormalities the results of the alteration of the gene function. Disease causing mutations have been identified in more than 1990 of the 3310 single gene disease. There are four effects of disease causing mutations on protein function. 1- Loss of function of a protein. 2-Gain a function. 3-Acquision of a novel property by mutant protein. 4- Expression of a gene at the wrong time or place. Examples of these effects: 1-α thalasemias are commonly examples for deletions of α globin genes. 2-Gain function mutations can alter the biochemical phenotype by increasing the function of a protein. This effect because of a-İncrease in the level of protein’s expression(Trisomy 21). b- İncrease in the ability of each protein to perform one or more normal function. Achondroplasia (fibroblast growth factor mutation active in the absence of the ligand). 3-Acquising of a novel property:In a few disease the change in amino acid sequence does not change function. Ex.Sickle cell disease(β chain:Glu6Val) no effect on on transport of oxygen but this hemoglobin chains aggregate when deoxigenated, it forms polymeric fibres. 4-Expression of a gene at the wrong time: the regulatory regions of the gene can alter and cause an inappropriate expression of the gene in normal time or place. ex oncogene normally promotes cell proliferation. But if is not normally expressed causes cancer. Some mutations in hemoglobin regulatory elements lead to the continued expression in the adult life γ globulin gene. This gama globulin is normally expressed at high levels only in fetal not postnatal life. This mutation led to phenotype called persistance of fetal hemoglobin. The molecular and Biochemical causes of genetic diseaes: Mutation protein coding genes(DNA)→mutation→Defective protein production. These are examples of single gene disorders. Some examples of proteins associated with monogenic diseases. Some examples of Classes of Proteins Associated with Monogenic Diseases 1-Transport and storage İnterorgan Hemoglobin (thalassemias)(AR) İntracellular transport (copper transport prot. menkes syndr. (AR) Epitel membr. Cystic fibrosis (CFRT AR) 2-Enzyme defects Amino acids - PKU(phenyl alanine hydroxilase AR) Complex lipid-Tay sachs(Hexosaminidase A AR) Purines-immundeficiency( Adenosine deaminidase AR) Carbohydrates Galactose 1 phosphate uridyl transferase 3-Structure of cells and organs Duschene muscular distrophy(dystrophin XR) 4-Control of growth and differantiation-Tumor suppressors,RB gene products (AR), oncogenes(AD). 5-Intracellular metabolism and comunication Growth gormon(dwarfizm,AR),insulin(AD) Familial hypercholesterolemia(LDL receptor). 1-Transport and Storage THALASSEMIAS Hemoglobin is the oxygen carrier in vertebrate red blood cells. The molecule contains four subunits 2 α , 2 βglobin chains Each subunit composed of polypeptide chain globin and prostetic group heme. Heme is a iron containing pigment that combines with oxygen to give the molecule its O transport ability. Thalassemia is drived from greek word of sea –Thalassa,miamediterenian origin. Hemoglobin A is normal adult hemoglobin 2 α 141 aa chain folded and fitted 2 β 146 aa Four chain folded and fitted The chains resemble each other. β thalassemias Decreasd β globin production causes hypochromic, microcytic anemia. Imbalance in globin synthesis leads to precipitation of excess α chains, leads damage of red cel membrane. β chain is important in post natal period. Onset of β thalassemia apperent untill a few monts after birth (β globin replaces γ ). Synthesis of Hb A reduces. Beta thalassemias usually single base pair mutations. They are so many different type of mutations. 1- 2β thalassemia-allel thalassemia major(severe anemia) 2-So little production of βglobin No Hb A present. β° thalassemia. 3- Some Hb A is detectable. β+ thalassemia 4-Carriers of one β+ thalassemia are clinically thalassemia minor. Thalassemia minor patients have hypochromic,microcytic red blood cells . They may have a slight anemia that can miss diagnosed. MOLECULAR BASIS OF β THALASSEMIA Simple β thalassemias results many different types of molecular abnormalities mostly point mutations in the β globin gene. Deletions -β globin gene deletions (619 base pair deletion) Defective mRNA synthesis - RNA splicing defects - promoter mutations - poly adenylation signal defects Nonfunctional mRNA - Nonsense mutations - Frameshift mutations TRANSPORT DEFECTS CYSTİC FİBROSİS Autosomal recessive genetic disorders in Caucasian population İncidence ~ 1/ 2500 CF gene (called CFTR - Cystic fibrosis conductance Regulatory protein) The protein encoded by the CTFR gene is a regulated Cl¯ channel located in the apical membrane of epithelia cells affected by the disease. PHENOTYPES Lungs, Pancreas (deficiency of pancreatic enzymes) Sweat glands (eleveted level of Cl. >60meq/lt) Chronic obstructive lung disease ( because of thick secretion and recurrent infection) Infertility (in male) Half of the patients survive to 26 years CF gene located on chorosome 7q31 spans about 250 kb DNA It has 27 exons Encode large integral protein 170 kD. Gene called CFTR CTFR Cl¯ channel has 5 domain: 1. MSD1 (membrane spaining domain) 2. MSD2 3. NBD1 ( nucleotid binding domain) (AT binding domain) 4. NBD2 5. Regulatory domain The pore of Cl channel is formed by the 12 transmembrane segments. ATP is bound and hydrolyzed by the NBDs. Energy released is used for ion transport. Regulation of the channel is mediated by phosphorylation of the R domain. It has 4 type mutation -class I : Defect in protein production Premature stop codons or mutations generates -class II : Defective protein processing due to misfolding of protein Deletion at phenylalanine residue at position 508 (∆F 508) The first ATP binding fold (NBD1) Accounts ~ 70% of CF allels GER → Golgi →Plasma membrane -class III : Mutations of the NBDs Defective regulation of protein S1255P (mutation at NBD2) -class IV : Mutation at regulatory domain Defective conduction due to alteration of Cl¯ channel (R334W) Detection and Treatment Detection of Na and Cl amount DNA mutation analysis Prenatal Diagnosis Population screening 2-ENZYME DEFECTS A-AMINOACIDOPATHIES Hyperphenylalainemias The abnormalities that lead to an increase in the blood level of phenylalaline, is called PKU. There is mutations at phenylalaline coding gene loci. There is loss of function mutations on the gene encoding PAH. PAH gene isolated in 1986, more than 400 different allels have been recognized. Phenylalaninehydroxylase gene mutations Arg 408 trp- activity<1% -- %31 european Tyr414Cys- activity30% -- %5 “ Ile 65 Thr -- activity 25% --%5 “ B-LYOSOSOMAL STORAGE DISEASES Lyososomes are membrane bound organels containing hydrolitic enzymes. They involved in the degradation of biologic macromolecules. Genetic defects in these hydrolases lead to the accumulation of their substrates in the lysosome. They lead cellular dysfunction-cell death . When brain is affected it causes neurodegeneration. There are more than 48 lyososome hydrolase. Almost all autosomal recessive. TAY-SACHS DISEASE Lyososomal storage disease (GM2 gangliosides) The inability to degrade a sphingolipid GM2 ganglioside. The biochemical lesion is deficiency of hexoaminidase A. The disease has its clinical impact especially on the brain. Hex A is the product of 3 gene system. α subunit Hex A β subunit Hex B genes Mutations of the Hex A Mutation Effect -4 bp insertion premature (exon 11) -Exon 12 splice Junction G→C homozygote phenotype Tay-Sachs stop codon defective mRNA spilicing Tay-Sachs 3-DISORDER OF STRUCTURAL PROTEINS DUCHENE-AND –BECKER MUSCULAR DISTROPHY Severe untreatable, relatively common X linked disorder. Related with Dystrophin protein. Affected boys normal at first year. Muscle weakness developed age 3-5. The child confined to wheelchair at age 12 and deads at the age of 20. Creatine kinase level is elevated 50100 times upper limit of normal Patients die of respiratory failure or cardiac failure, brain is also effected. Becker (BMP) is also due to mutation in dystrophin gene İt produces a phenotype is much milder. If patients is still walking at the age of 16 the disease is BMD. İncidence of DMDis 1 in 3300 live male birth Calculated mutation rate is (10)-4 Normal male produces sperm with new mutation of DMD gene every 10 to 11 seckonds(mens produces 8.107 sperm/day) Carier females have no clinical manifestations. 70% have↑creatine kinase İn rare instances females have been reported with DMD. Size of DMD gene 2300 kb %1.5 of X chromosome Gene is a complex gene it have 79 exons 7 tissue spesific promoter. It encodes 427 kD protein. Mechanism of mutation in Duchenne or Becker muscular distrophy Gene deletion %60 dmd or bmd Point mut %34 " Partial duplication %6 "