CLASSES OF BIOMOLECULES
AFFECTED IN DISEASE
M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar
Classes of Biomolecules
Affected in Disease
 All classes of biomolecules found in cells are affected
in structure, functi...
Rate of Biochemical Alterations
 Biochemical alterations that cause disease may
occur rapidly or slowly
 Cyanide (inhibi...
Deficiency or Excess of
Biomolecules
 Diseases can be caused by deficiency or excess
of certain biomolecules
 deficiency...
Organelle Involvement
 Almost every cell organelle has been involved in
the genesis of various diseases
Different Mechanisms, Similar
Effect Different biochemical mechanisms can produce
similar pathologic, clinical, and labor...
Genetic Diseases
 Many disease are determined genetically
 Three major classes: (1) chromosomal disorders, (2)
monogenic...
Genetic Diseases
 Polygenic denotes disorder caused by multiple
genetic factors independently of environmental
influences...
Chromosomal Disorders
 Excess or loss of chromosomes, deletion of part
of a chromosome, or translocation
 e.g., Trisomy ...
Monogenic Disorders
 Involve single mutant genes
 Classification:
(1) autosomal dominant - clinically evident if one
chr...
Multifactorial Disorders
 Interplay of number of genes and environmental
factors
 pattern of inheritance does not confor...
Inborn Error of Metabolism
 A mutation in a structural gene may affect the
structure of the encoded protein
 If an enzym...
Inborn Error of Metabolism
 A block can have three results:
(1) decreased formation of the product (P)
(2) accumulation o...
Inborn Error of Metabolism
 Phenylketonuria - mutant enzyme is usually
phenylalanine hydroxylase
 synthesize less tyrosi...
Genetic Linkage Studies
 The more distant two genes are from each other on the
same chromosome, the greater the chance of...
Genetic Linkage Studies
• Simple sequence repeats (SSRs), or
microsatellites, small tandem repeat
units of 2-6 bp are more...
Methods to clone disease genes
 Functional approach
 gene identified on basis of biochemical defect
 e.g., found that p...
Methods to clone disease genes
 Positional cloning
 no functional information about gene product,
isolated solely by it ...
Identifying defect in disease
gene
 Once disease gene identified, still can be
arduous task identifying actual genetic de...
Ethical Issues
 Once genetic defect identified, no treatment options
may be available
 Will patients want to know?
 Is ...
Molecular Medicine
 Knowledge of human genome will aid in the
development of molecular diagnostics, gene
therapy, and dru...
Gene expression in diagnosis
 Diffuse large B-cell lymphoma (DLBCL),
a disease that includes a clinically and
morphologic...
Treatment for Genetic Diseases
 Treatment strategies
(1) correct metabolic consequences of disease by
administration of m...
Gene Therapy
 Only somatic gene therapy is permissible in
humans at present
 Three theoretical types of gene therapy
 r...
Gene Therapy
 Three major routes of delivery of genes into humans
(1) retroviruses
 foreign gene integrates at random si...
Gene Therapy
(2) adenoviruses
 replication-deficient
 does not integrate into host cell genome
 disadvantage: expressio...
Gene Therapy
 Conclusions based on recent gene therapy trials
 gene therapy is feasible (i.e., evidence for expression
o...
Genetic Medicines
 Antisense oligonucleotides
 complementary to specific mRNA
sequence
 block translation or promote
nu...
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Genetic disesase

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The Hardy-Weinberg Law states that the genotypes in the population from one generation to another generation will be in equilibriym.

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Genetic disesase

  1. 1. CLASSES OF BIOMOLECULES AFFECTED IN DISEASE M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar
  2. 2. Classes of Biomolecules Affected in Disease  All classes of biomolecules found in cells are affected in structure, function, or amount in one or another disease  Can be affected in a primary manner (e.g., defect in DNA) or secondary manner (e.g., structures, functions, or amounts of other biomolecules)
  3. 3. Rate of Biochemical Alterations  Biochemical alterations that cause disease may occur rapidly or slowly  Cyanide (inhibits cytochrome oxidase) kills within a few minutes  Massive loss of water and electrolytes (e.g., cholera) can threaten life within hours  May take years for buildup of biomolecule to affect organ function (e.g., mild cases of Niemann-Pick disease may slowly accumulate sphingomyelin in liver and spleen)
  4. 4. Deficiency or Excess of Biomolecules  Diseases can be caused by deficiency or excess of certain biomolecules  deficiency of vitamin D results in rickets, excess results in potentially serious hypercalcemia  Nutritional deficiencies  primary cause - poor diet  secondary causes - inadequate absorption, increased requirement, inadequate utilization, increased excretion
  5. 5. Organelle Involvement  Almost every cell organelle has been involved in the genesis of various diseases
  6. 6. Different Mechanisms, Similar Effect Different biochemical mechanisms can produce similar pathologic, clinical, and laboratory findings  The major pathological processes can be produced by a number of different stimuli  e.g., fibrosis of the liver (cirrhosis) can result from chronic intake of EtOH, excess of copper (Wilson’s disease), excess of iron (primary hemochromatosis), deficiency of 1-antitrypsin, etc.  different biochemical lesions producing similar end point when local concentration of a compound exceeds its solubility point (excessive formation or decreased removal) precipitation to form a calculus  e.g., calcium oxalate, magnesium ammonium phosphate, uric acid, and cystine may all form renal stone, but accumulate for different biochemical reasons
  7. 7. Genetic Diseases  Many disease are determined genetically  Three major classes: (1) chromosomal disorders, (2) monogenic disorders (classic Mendelian), and (3) multifactorial disorders (product of multiple genetic and environmental factors)
  8. 8. Genetic Diseases  Polygenic denotes disorder caused by multiple genetic factors independently of environmental influences  Somatic disorders - mutations occur in somatic cells (as in many types of cancer)  Mitochondrial disorders - due to mutations in mitochondrial genome
  9. 9. Chromosomal Disorders  Excess or loss of chromosomes, deletion of part of a chromosome, or translocation  e.g., Trisomy 21 (Down syndrome)  Recognized by analysis of karyotype (chromosomal pattern) of individual (if alterations are large enough to be visualized)  Translocations important in activating oncogenes  e.g., Philadelphia chromosome - bcr/abl)
  10. 10. Monogenic Disorders  Involve single mutant genes  Classification: (1) autosomal dominant - clinically evident if one chromosome affected (heterozygote)  e.g., Familial hypercholesterolemia (2) autosomal recessive - both chromosomes must be affected (homozygous)  e.g., Sickle cell anemia (3) X-linked - mutation present on X chromosome  females may be either heterozygous or homozygous for affected gene  males affected if they inherit mutant gene
  11. 11. Multifactorial Disorders  Interplay of number of genes and environmental factors  pattern of inheritance does not conform to classic Mendelian genetic principles  due to complex genetics, harder to identify affected genes; thus, less is known about this category of disease  e.g., Essential hypertension
  12. 12. Inborn Error of Metabolism  A mutation in a structural gene may affect the structure of the encoded protein  If an enzyme is affected, an inborn error of metabolism may result  A genetic disorder in which a specific enzyme is affected, producing a metabolic block, that may have pathological consequences
  13. 13. Inborn Error of Metabolism  A block can have three results: (1) decreased formation of the product (P) (2) accumulation of the substrate S behind the block (3) increased formation of metabolites (X,Y) of the substrate S, resulting from its accumulation  Any one of these three results may have pathological effects S P Increased S Decreased P E Normal Block Increased X,Y *E
  14. 14. Inborn Error of Metabolism  Phenylketonuria - mutant enzyme is usually phenylalanine hydroxylase  synthesize less tyrosine (often fair skinned), have plasma levels of Phe, excrete phenylpyruvate and metabolites  If structural gene for noncatalytic protein affected by mutation can have serious pathologic consequences (e.g., hemoglobin S) Increased phenylalanine Decreased tyrosine Block Increased phenylpyruvic acid *E
  15. 15. Genetic Linkage Studies  The more distant two genes are from each other on the same chromosome, the greater the chance of recombination occurring between them  To identify disease-causing genes, perform linkage analysis using RFLP or other marker to study inheritance of the disease (marker)
  16. 16. Genetic Linkage Studies • Simple sequence repeats (SSRs), or microsatellites, small tandem repeat units of 2-6 bp are more informative polymorphisms than RFLPs; thus currently used more
  17. 17. Methods to clone disease genes  Functional approach  gene identified on basis of biochemical defect  e.g., found that phenotypic defect in HbS was Glu Val, evident that mutation in gene encoding -globin  Candidate gene approach  genes whose function, if lost by mutation, could explain the nature of the disease  e.g., mutations in rhodopsin considered one of the causes of blindness due to retinitis pigmentosa
  18. 18. Methods to clone disease genes  Positional cloning  no functional information about gene product, isolated solely by it chromosomal position (information from linkage analysis  e.g., cloning CF gene based on two markers that segregated with affected individuals  Positional candidate approach  chromosomal subregion identified by linkage studies, subregion surveyed to see what candidate genes reside there  with human genome sequenced, becoming method of choice
  19. 19. Identifying defect in disease gene  Once disease gene identified, still can be arduous task identifying actual genetic defect Mutations in CFTR gene Structure of CFTR gene and deduced protein
  20. 20. Ethical Issues  Once genetic defect identified, no treatment options may be available  Will patients want to know?  Is prenatal screening appropriate?  Will identification of disease gene affect insurability? • e.g., Hungtington’s disease - mutation due to trinucleotide (CAG) repeat expansion (microsatellite instability) – normal individual (10 to 30 repeats) – affected individual (38 to 120) - increasing length of polyglutamine extension appears to correlate with toxicity
  21. 21. Molecular Medicine  Knowledge of human genome will aid in the development of molecular diagnostics, gene therapy, and drug therapy
  22. 22. Gene expression in diagnosis  Diffuse large B-cell lymphoma (DLBCL), a disease that includes a clinically and morphologically varied group of tumors that affect the lymph system and blood. Most common subtype of non- Hodgkin’s lymphoma.  Performed gene-expression profiling with microarray containing 18,000 cDNA clones to monitor genes involved in normal and abnormal lymphocyte development  Able to separate DLBCL into two categories with marked differences in overall patient survival.  May provide differential therapeutic approaches to patients
  23. 23. Treatment for Genetic Diseases  Treatment strategies (1) correct metabolic consequences of disease by administration of missing product or limiting availability of substrate  e.g., dietary treatment of PKU (2) replace absent enzyme or protein or to increase its activity  e.g., replacement therapy for hemophilia (3) remove excess of stored compound  e.g., removal of iron by periodic bleeding in hemochromatosis (4) correct basic genetic abnormality  e.g., gene therapy
  24. 24. Gene Therapy  Only somatic gene therapy is permissible in humans at present  Three theoretical types of gene therapy  replacement - mutant gene removed and replace with a normal gene  correction - mutated area of affected gene would be corrected and remainder left unchanged  augmentation - introduction of foreign genetic material into cell to compensate for defective product of mutant gene (only gene therapy currently available)
  25. 25. Gene Therapy  Three major routes of delivery of genes into humans (1) retroviruses  foreign gene integrates at random sites on chromosomes, may interrupt (insertional mutagenesis) the expression of host cell genes  replication-deficient  recipient cells must be actively growing for integration into genome  usually performed ex vivo
  26. 26. Gene Therapy (2) adenoviruses  replication-deficient  does not integrate into host cell genome  disadvantage: expression of transgene gradually declines requiring additional treatments (may develop immune response to vector)  treatment in vivo, vector can be introduced into upper respiratory tract in aerosolized form (3) plasmid-liposome complexes
  27. 27. Gene Therapy  Conclusions based on recent gene therapy trials  gene therapy is feasible (i.e., evidence for expression of transgene, and transient improvements in clinical condition in some cases  so far it has proved safe (only inflammatory or immune reactions directed toward vector or some aspect of administration method rather than toward transgene  no genetic disease cured by this method  major problem is efficacy, levels of transgene product expression often low or transient
  28. 28. Genetic Medicines  Antisense oligonucleotides  complementary to specific mRNA sequence  block translation or promote nuclease degradation of mRNA, thereby inhibit synthesis of protein products of specific genes  e.g., block HIV-1 replication by targeting gag gene  Double-stranded DNA to form triplex molecule

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