1. Genetic Basis of Diseases
Atif Hassan Khirelsied Ph.D.
Atif H Khi l i d Ph D
Department of Biochemistry
D f Bi h i
Faculty of Medicine
International University of Africa, Khartoum, Sudan
l f f h d

2. Learning objectives
Learning objectives
• Understand the common processes that lead to
mutagenesis
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• Appreciate how different classes of mutations yield
different effects on protein structure and function.

3. Learning objectives
Learning objectives
• Draw out example pedigrees representing
1.
1 autosomal dominant
dominant,
2. autosomal recessive,
3. X‐linked dominant,
4. X linked recessive, holandric
4 X‐linked recessive holandric
5. and mitochondrial inheritance.

4. Learning objectives
Learning objectives
• Appreciate the concept of heritability in the context of
complex diseases.
• Identify the common chromosomal disorders and
define aneuploidy, triploidy, trisomy and monosomy,
with examples of diseases.
• Understand the molecular biology of cancer and
Understand the molecular biology of cancer and
describe features suggestive of inherited cancer
suscept b ty
susceptibility.

5. Genetic disorders
Genetic disorders
• Genetic disorders are illnesses caused by
abnormalities in genetic sequences and the
b liti i ti d th
chromosome structures.

6. Genetic disorders
Genetic disorders
Burden
• Although each genetic disorder may be rare,
combined together genetic diseases are common.
combined together genetic diseases are common
• Can affect any body system and have a major impact
on both morbidity and mortality.

7. Genetic disorders
Genetic disorders
Importance of medical genetics
• An understanding of genetics is important, not only
for the diagnosis and management of such
disorders, but also for the identification of genetic
disease carriers for genetic counseling
disease ‘carriers’ for genetic counseling .

8. MUTATION
• Mutations are permanent inheritable changes in the
amount or structure of genetic material.
t t t f ti t i l
• They can be inherited or occur spontaneously and
can be subdivided into germline (gametes) or
somatic mutations.

9. MUTATION
• Mutation plays a key role in the pathogenesis of
genetic disorder, by altering gene sequences and
ti di d b lt i d
their protein products.
p p
• Defective gene→ defective protein → altered
function → disease

10. Mechanisms of mutation
Mechanisms of mutation
• At the single‐gene level mutations may result from:
– substitution (point mutation)
– deletion
– insertion
– inversion
– triplet repeat expansion.

11. Substitution mutation
Substitution mutation
• Point mutations may arise as a result of:
1. Errors in DNA replication.
2. Defective repair of damaged DNA.
2 D f ti i fd d DNA
3. Spontaneous deamination of methylated
3 Spontaneous deamination of methylated
cytosine to thymine (most common) .

12. Substitution mutation
Substitution mutation
• Substitutions are classified as:

13. Substitution mutation
Substitution mutation
• Point mutations may be silent or deleterious
depending upon their type and site.
d di th i t d it
• Rarely, a mutation may be advantageous and favored
by natural selection.

14. Mutations

15. Deletion and insertion
Deletion and insertion
• Deletion is loss of DNA involving from one to many
thousands of base pairs.
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• Sequences at the ends of deletions are often similar,
predisposing to recombination errors.

16. Deletion and insertion
Deletion and insertion
• Insertion is a gain of DNA.
• Duplication a type of insertion occurs when runs of
Duplication, a type of insertion, occurs when runs of
bases and repeated motifs predispose to duplication
by replication slippage

17. Deletion and insertion
Deletion and insertion
The effects on the protein of deletion and insertion
depend on:
– The amount of material lost
The amount of material lost
– Whether the reading frame is affected.
Whether the reading frame is affected.

18. Deletion
Duplication

19. Deletion and insertion
Deletion and insertion
• Deletion, Alport’s syndrome, a hereditary disease of
basement membranes, characterized by
b t b h t i db
sensorineural deafness and renal failure.
• Duplication, Duchenne muscular dystrophy (DMD).

20. Inversion
• Inversions may involve anything from two to many
thousands of base pairs.
• They occur in areas of sequence homology
They occur in areas of sequence homology
(sequences at each end of the inverted segment
o e ese b e eac o e )
often resemble each other).
• In haemophilia A 40% of mutations result from an
In haemophilia A, 40% of mutations result from an
inversion of several hundred thousand base pairs
within the factor VIII gene
within the factor VIII gene

21. Triplet repeat expansions
Triplet repeat expansions
• T i l t t i l tid repeat expansions are
Triplet or trinucleotide t i
typically involving CG‐rich trinucleotides (CGG, CCG,
CAG,CTG).
CAG CTG)
• Triplet expansion results in a defective gene product,
yielding disease.
• These expansions may be inherited in an
These expansions may be inherited in an
autosomally dominant or recessive manner, or be X‐
linked.
linked

22. Triplet repeat expansions
Triplet repeat expansions
• EXAMPLE
• Friedreich’s ataxia results from an expansion of the
(GAA) within the first intron of the FXN gene.
(GAA) within the first intron of the FXN gene
• N
Normally there are 8 to 30 copies of this trinucleotide,
ll h 8 30 i f hi i l id
patients may have as many as 1000.
• This expansion is intronic and is thought to make the
DNA ‘sticky’, interfering with the process of
transcription.

23. Structural effects of mutation
on protein
• Silent mutations
• Silent mutations, point mutations, have no effect on
the aminoacid sequence of a protein.
• Considered to be ‘evolutionary neutral’, but recently
demonstrated to exert an effect on the control of
demonstrated to exert an effect on the control of
differential splicing.

24. Structural effects of mutation
on protein
• Missense mutations
• A base change alters a codon, incorporation of a different
amino acid into the protein.
amino acid into the protein
• The effect of the mutation on protein function depends
The effect of the mutation on protein function depends
upon its location relevant to the tertiary or quaternary
structure of the protein
structure of the protein
• It l d
It also depend on whether the two amino acids involved
d h th th t i id i l d
are from the same or different groups (i.e. hydrophobic or
hydrophilic).
hydrophilic)

25. Structural effects of mutation
on protein
Exammple
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• In sickle‐cell disease, the substitution of A by T at the
i kl ll di h b f b h
17th nucleotide of the β‐globin gene changes the codon
from GAG to GTG (Glu to val).
from GAG to GTG (Glu to val)
• This mutation changes the solubility and molecular
This mutation changes the solubility and molecular
stability of the protein.
• Haemoglobin forms polymers under conditions of low
oxygen tension, leading to sickling of red blood cells.
yg , g g

26. Structural effects of mutation
on protein
Nonsense mutations
• Nonsense mutations are point mutations that lead to
the conversion of a codon to a stop codon
the conversion of a codon to a stop codon (UAG,
• UAA, UGA).
• They lead to a truncated protein, with those that
occur early in a gene sequence having a higher
probability of completely inactivating a gene.

27. Structural effects of mutation
on protein
• Frameshift mutations
• Insertions and deletions of nucleotides, if not a
i dd l i f l id if
multiple of three, lead to ‘frameshift’ mutations,
• The open reading frame of the gene and the
corresponding amino‐acid sequence is altered,
di i id i l d
• Leading to complete inactivation of the gene.

28. Functional effects of mutation
on protein
• With the exception of imprinted genes, genes on both
the maternal and paternal chromosomes are
expressed.
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• If either the maternal or the paternal gene contains a
mutation, the cell will express two different protein
products.

29. Functional effects of mutation
on protein
• Mutations exert their phenotypic effects by one of
two mechanisms:
1. loss of function
2. or gain of function.

30. Functional effects of mutation
on protein
• Loss of function mutations
– Amorphic mutation also known as ‘null
mutations , are associated with a complete
mutations’, are associated with a complete
absence of gene product function.

31. Functional effects of mutation
on protein
• L
Loss of function mutations
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– Hypomorphic mutation, also known as ‘leaky
mutations’, lead to a partial loss of function.
– They usually result from:
1. an altered amino acid that makes the polypeptide
less active.
2. a reduction in transcription that results in less
normal transcript.

32. Functional effects of mutation
on protein
Haploinsufficiency
• The majority of heterozygous states are haplosufficient;
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that is one functional copy of a gene is adequate for the
manifestation of a wild type phenotype.
manifestation of a wild type phenotype
• The term haploinsufficiency is a situation whereby a
reduction of 50% of gene function results in an abnormal
phenotype.
h t

33. Functional effects of mutation
on protein
• Gain of function mutations
Gain of function mutations
• These mutations result in either:
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– increased activity of the gene product (hypermorphic)
– Or the gain of a novel function or a novel pattern of
O e ga o a o e u c o o a o e pa e o
gene expression of the gene product (neomorphic).

34. Functional effects of mutation
on protein
• Gain of function mutations
Gain of function mutations
• Trinucleotide repeat expansions represent gain of
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function mutations.
• Usually a toxic gain of protein function, which
predisposes to protein misfolding and protein
aggregation and leads to neurodegeneration.

35. Functional effects of mutation
on protein
• Dominant negative mutations
• Dominant negative mutations are also known as
antimorphic mutations.
• They arise when the null allele product of a
They arise when the null allele product of a
heterozygote adversely affects the normal gene
product, for example by dimerizing with and
product, for example by dimerizing with and
inactivating it.

36. Functional effects of mutation
on protein
• Dominant negative mutations
• The classical example is that of an amino‐acid change
that prevents a polypeptide from functioning in a
multimeric protein complex as seen with fibrillin in
protein complex, as seen with fibrillin in
Marfan syndrome.