Genetic pdf - د. فائزة

Genetic disorders

Robbins Basic Pathology
Ch 6
P 215

Dec. 7

. 2015

Genetic disorders

Objectives

• Introduction
• Mutations
• Structure & No. variations in genes
• Epigenetic changes.
• Types of genetic disorders
• Genes encoding structural pr.
   Marfan Syndrome “MFS”
   Ehlers- Danlos Syndrome “EDSs”
• Genes encoding receptor proteins’ or channels.
   Familial hypercholestremia.

Almost

all diseases

have a genetic

component.

Diseases cause

long term morbidity

are

genetically determined

50%

of spontaneous abortuses have a

genetic component.

DNA, chromosomes and chromatin

• In the nucleus, the

DNA

double helix is packaged

by special proteins

(histones)

to form a complex

called

chromatin

• The chromatin undergoes further condensation

to form the

chromosome

• DNA is double-stranded, with the

exception of the ends of
chromosomes, of single stranded
DNA, called

telomeres

• Telomeres

prevent degradation and

accidental fusion of chromosomal

DNA

Human ch. (grey) capped by
telomeres (white)

Telomere

The human diploid

karyotype

, showing the organization of the

genome

into chromosomes. shows both the female (XX) and male (XY) versions of
the 23rd chromosome pair.

• Genome;

all genetic data of a single cell. The genes in the

nucleus, & mitochondrial DNA.

(23 identical chromosomal pairs + Mitoch DNA)

• Genes;

is a section of the genome which codes for one

protein. It consists of various codons.

•

Codon;

Every codon consists of three adjacent

nucleotides.

• 3 Bases

• in order of increasing scale, we have: base -

codon - gene - chromosome - genome

• A genome is all genetic data of a single cell. That

includes the genes in the nucleus, but also that of
mitochondrial DNA.
A gene is a section of the genome which codes for
one protein. It consists of various codons.

• A set of three bases on a single strand of DNA is

called a "codon". This is because it codes for a
particular amino acid when the codon is transferred
to RNA and then used to construct a protein

3 Bases - codon - gene - chromosome - genome.

Genes are expressed by being transcribed into RNA,
and this RNA then translated into protein.

codon
3

bases

gene

Mitochondrial DNA

• All Mit DNA is derived from the mother as

sperm contribute no mitochondria to the
Zygote.

DISEASES

• GENETIC
• ENVIRONMENTAL
• BOTH

 Hereditary (familial) disorders

Congenital diseases

Classes of genetic variants:
Mutations

genetic variations that cause diseases.

• germ cells

• somatic cells
Polymorphisms;

genetic variations that do not

cause disease

• single gene is insufficient to produce the disease.
• when several polymorphisms are present, disease

occurs, hence the term

multigenic or polygenic

Classes of Mutations
Nucleotide Substitution
• Synonymous

– resulting in a change in the codon

but no change in the AA and thus no phenotype

•

Missense

– change in the codon, resulting in an

A.A change in the protein

•

Nonsense

– introducing a premature stop codon,

resulting in truncation of the protein

Point mutation - missense mutation

• Substitution of a

single nucleotide base

by a different base,

(

Sickle Cell anemia)

Point mutation - nonsense mutation

•

Change an

AA codon

a chain termination codon, or

stop codon

--- interrupt translation & the resultant protein

are rapidly degraded (

B Thalasemia)

Frameshift mutation

Insertion or deletion of 1 or 2 or > base pair alter the
reading frame of the DNA strand

Four-base insertion

• Four-base insertion in the hexosaminidase A

gene, leading to a frameshift mutation. This
mutation is the major cause of Tay-Sachs
disease in Ashkenazi Jews.

Classes of Mutations
• Trinucleotide repeat mutations

mplification of sequence of 3 nucleotide

• e.g in fragile X syndrome, there are 250-4000 repeats of

the sequence CGG within the gene called FMR-1.

• In the normal population, the number of repeats is

small 29, so amplification of FMR-1 giving rise to mental
retardation

Classes of Mutations
Structure & Numerical variations in genes

• Germ line or Somatic cells.
• Amplification
• Deletion
• Insertion
• Translucation

 Polymorphism or Mutation

Classes of Mutations
 Numerical chromosomal abnormality

e.g. Trisomy of Chromosome 21 (Downs

Syndrome).

 Epigenetic Changes

• Modulation of genetic expression in absence of mutation

or structural changes.

• Don’t alter the sequence of the DNA code but have

biological effect in gene function.

• Histone Methylation
• Methylation, phosphorelation or acetylation.
• Affect on tumor suppressor gene

Cancer

• Cause progression of cancer.



Karyotype

 Phenotype

Penetrance:

• Proportion of individual bearing a mutant allele

who develop the disease phenotype

 Expression:
•

The degree of severity of dis expression

• E.g. NF 100% pentrance with variable expressiomn.

Neurofibromatosis

Fully (100%) penetrant
VARIABLE EXPRESSIVITY

•

The

Environmental factors

• and/or Variation in other genes

that act as modifiers of the

mutated gene’s

Types of genetic diseases

Mutation in single gene;

Mendelian disorders. Single

gene mutations. highly penetrant,

2- Diseases arising from abnormality in No. or structure

of chromosome. high penetrance

3- Diseases with

multifactorial inheritance

(genetic &

environmental) .

Heterogenous group

that is single gene but do not

follow Mendelian rules of inheritance.

e.g. Mutation in mitoch. DNA, Triple repeat mutation,

epigenetic (genomic imprinting).

 Complex multifactorial disorders

• more common .
• interactions between multiple variant genes &

environmental factors.

• low penetrance.
• multifactorial disorders.

• Atheroscl., DM, hypertension, & autoimmune diseases.
• Even normal traits such as height and weight are governed

by polymorphisms in several genes.

• Multifactorial disorders = Multigenic (several polymorphic

genes) + Environmental factors

Diseases caused by single gene defects

include:

• 1% of adult admission to hospital.
• 6 – 8 % of pediatric admission.

* AR
* X-linked diseases

AUTOSOMAL DOMINANT

• Disease is in

Heterozygote

• Healthy parent

(New Mutation)

• PENETRANCE.

• VARIABLE EXPRESSIVITY,

(e.g. Neurofibromatosis)

The

environmental factors and/or variation in other

genes

that act as modifiers of the mutated gene’s function

????

BOTH SEXES INVOLVED

- GENERATIONS NOT SKIPPED

Neurofibromatosis

Fully (100%) penetrant
VARIABLE EXPRESSIVITY

The

environmental factors and/or variation in other genes

that act as

modifiers of the mutated gene’s function are mostly unknown.



Examples of AD disorders:

• Marfan syndrome
• hypercholesterolemia
• Polycystic kidney disease
• Hereditary spherocytosis
• Familial polyposis coli

AUTOSOMAL RECESSIVE

• Largest group of Mendelian disorders
• Disease in

HOMOZYGOTES

• Often

COMPLETE PENETRANCE

• Onset usually

EARLY in life

• Proteins show

LOSS of FUNCTION

• Include ALL

Inborn Errors of Metabolism

BOTH SEXES INVOLVED

- GENERATIONS SKIPPED

• Examples of AR disorders:

• Sickle cell anemia
• Thalassemias
• Cystic fibrosi
• Phenylketonuria
• Wilson disease
• Glycogen storage diseases
• Albinism