Molecular and Genetic Factor in Disease

moleculor and genetic factors in diseases

Introduction

Molecular medicine

• Is a broad field, where physical, chemical, biological and medical techniques are used to:
• Describe molecular structures and mechanisms
• Identify molecular and genetic errors of disease
• Develop molecular interventions to correct them. The molecular medicine perspective emphasizes cellular and molecular phenomena and interventions rather than the previous conceptual and observational focus on patients and their organs

Classification of Human diseases

• Those that is genetically determined.
• Those that is almost entirely environmentally determined.
• And those to which both nature and nurture contribute.
• About 1% of all newborn infants possess a gross chromosomal abnormality.
• Approximately 5% of individuals under age 25 develop a serious disease with a significant genetic component

The human genome

• The gene is the most important unit of genetics.
• The estimated total number of genes is about 30000- 35000, the gene has an average 1400 base pairs,only 1.5% of the genome reprsents primary coding sequence
• There are 3×109 (3000 megabase) base pairs of deoxy- ribonucleic acid (DNA) present In the human genome.
• DNA forms a double stranded helical structure with only two type of base pairing are possible G-C and A-T, the double stranded DNA unit of two nucleotides is referred as a (BASE PAIR (bp))


The double stranded DNA helix is coiled around chromosomal protein called histone to form nucleosomes then these also adopt a coiled structure to form a chromatin fiber which on more coiling forms the chromosome
DNA contains all of the genetic information required for the development of cells into tissue & organs
Human cells contain 46 chromosomes:
22 pairs of autosomes and 1 pair of sex chromosome One chromosome of each pair is derived from each parent; these 46 chromosomes are the diploid number seen in somatic cells.
Only germ cells (sperm &ova) have the haploid number of 23 chromosome (22 autosomes and either an X or Y)

• The genetic code is a 3 nucleotides unit which specify certain aminoacid to be inserted into protein ,only a very small fraction of the human genome codes for protein;
• a Locus refers to any area of the genome ,
• not all the DNA code for protein
• sequences within the gene include coding regions(exons),noncoding regions(introns)and regulatory sequences
• The conversion of DNA sequence to protein is mediated by RNA

• Most of the natural variation in DNA sequence occurs in the noncoding region and have no effect on development and function ,
• variations that occur in the coding region leads to change in protein sequence and possibly the function
• If DNA variation results in sufficient impairment of protein function to bring a harmful effect then A GENETIC DISEASE may result.
When the genetic abnormality is mild, the genetic disease can be recognized, but sometimes the genetic abnormality may impair more vital process to such an extent that embryogenesis cannot continue

X inactivation

• Is a special property of the X chromosome in the female one of the two X chromosome in a cell is inactive, so in a similar manner to male ,females only express one copy of genes on the X chromosomes and this process of inactivation is random ,This can have a bearing on the expression of diseases which are due to mutations in genes on the X chromosome as either the normal or the mutant gene may be inactivated.
• Genotype: is the genetic makeup of an individual (the sequences of their gene)
• Phenotype: is any aspect of structure or development of an individual (is the "outward, physical manifestation" of the organism)


Genomic imprinting
• It means that the effect of a gene depends on whether its inherited from the mother or father
• If an imprinted gene carries a mutation then the manifestation of the disease will vary according to which parent transmitted the mutation. For example a certain region on chromosome 15 contain several genes in which only the paternal or maternal allel
• is transcriptionally active so deletion of these gene on the paternal chromosome cause a syndrome called (prader willi syndrome) while deletion of maternal chromosome causes a different syndrome(angelman's syndrome)

Polymorphism

• It represents a small change in DNA sequence that does not result in overt diseases this can happen if:
• The change occurs in the noncoding DNA.
• Do not alter the amino acid inserted in a given protein.
• Result in an amino acid which is able to perform the same function as the original.
• We all share genome sequence that are 99.9% identical, the remaining 0.1% is therefore responsible for all genetic diversity between individuals.

Genetic factors in common diseases

• Susceptibility to many common diseases is influenced by genetic factors, this is recognized by an increased incidence of the diseases in first degree relatives of affected individuals but not in a pattern typical of classical single gene disorders
• Asthma, hypertension, diabetes, atopy , and ischemic heart diseases and many infectious diseases show this pattern
• Genes that act together with environmental influences giving rise to this susceptibility are of interest

• Penetrance and expression

• Individuals who inherit a specific disease mutation do not show an identical phenotype since they may not share the other genetic or environmental factors that predispose or unmask the full effect of the mutation.
• Penetrance is the proportion of individuals who develop the diseases phenotype.
• Fully penetrant mutation: if all individual who inheret it Develop the associated disease phenotype.
• If additional environmental factors are needed the gene may show late onset pentrance
• Non –pentrant mutation if the individual is not exposed to sufficient additional factors
• Disease Expression describes the degree to which the severity of the disease phenotype varies.


Genetic counseling
• Genetic counseling is providing information about the medical and family implications of a specific disease.
• Aims of Genetic counseling is to:
• Help individuals make decisions about planning a family
• Taking part in screening program
• Accepting prophylactic therapies.
• Specific problems encountered in genetic counseling include:
• Accurate assessment of genetic risk
• Identification of children at risk of genetic disorders
• The increase in genetic risks associated with consanguinity
• Non-paternity as an accidental finding in DNA diagnostic tests

Indication of genetic counseling

One or more birth defects
A genetic disorder or chromosome abnormality
Intellectual Development Disorder or developmental delay
Neuromuscular abnormalities
Unexplained metabolic problems
Congenital or familial hearing loss or blindness
Abnormal growth patterns
Abnormal sexual development
Prenatal exposure to drugs or medications
Cancer


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