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Molecular pathology: Physiopathology effect of Mutations. Dr Pupak Derakhshandeh, PhD Ass Prof of Medical Science of Tehran University. Mutations. changes to the either DNA or RNA caused by copying errors in the genetic material: Cell division Ultraviolet Ionizing radiation

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Molecular pathology physiopathology effect of mutations

Molecular pathology:Physiopathology effect of Mutations

Dr PupakDerakhshandeh, PhD

Ass Prof of Medical Science of Tehran University


  • changes to the either DNA or RNA

  • caused by copying errors in the genetic material:

    • Cell division

    • Ultraviolet

    • Ionizingradiation

    • chemical mutagens

    • Viruses

By aspect of phenotype affected morphological mutations
By aspect of phenotype affectedMorphological mutations

  • usually affect the outward appearance of an individual

  • Mutations can change the height of a plant or change it from smooth to rough seeds.

  • Biochemical mutations result in lesions stopping the enzymatic pathway

  • Often, morphological mutants are the direct result of a mutation due to the enzymatic pathway

Special classes conditional mutation
Special classesConditional mutation

  • wild-type or less severe phenotype under certain "permissive" environmental conditions

  • a mutant phenotype under certain "restrictive" conditions

  • For example: a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deletirious consequences at a lower temperature (permissive condition).


  • Nomenclature of mutations specify the type of mutation

  • and base or amino acid changes

  • Amino acid substitution: (e.g. D111E)

    • The first letter is the one letter code of the wildtype amino acid

    • the number is the position of the amino acid from the N terminus

    • the second letter is the one letter code of the amino acid present in the mutation

    • If the second letter is 'X', any amino acid may replace the wild type


  • Amino acid deletion: (e.g. ΔF508)

    • The Greek symbol Δ or 'delta' indicates a deletion

    • The letter refers to the amino acid present in the wildtype

    • the number is the position from the N terminus of the amino acid were it to be present as in the wildtype

Harmful mutations
Harmful mutations

  • Changes in DNA caused by mutation can cause errors in protein sequence

    • creating partially or completely non-functional proteins

  • To function correctly, each cell depends on thousands of proteins to function in the right places at the right times

  • a mutation alters a protein that plays a critical role in the body

  • A condition caused by mutations in one or more genes is called a genetic disorder

  • only a small percentage of mutations cause genetic disorders

  • most have no impact on health

    • For example, some mutations alter a gene's DNA base sequence but don’t change the function of the protein made by the gene

Dna repair system
DNA repair system

  • Often, gene mutations that could cause a genetic disorder

  • repaired by the DNA repair system of the cell

  • Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA

  • Because DNA can be damaged or mutated in many ways:

    • the process of DNA repair is an important way in which the body protects itself from disease

Beneficial mutations
Beneficial mutations

  • A very small percentage of all mutations :

    • have a positive effect

  • lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment:

    • For example, a specfic 32 base pair deletion in human Chemokine ReceptorCCR5 (CCR5-32) confers HIV resistance to homozygotes

    • delays AIDS onset in heterozygotes

    • The CCR5 mutation is more common in those of European descent

    • One theory for the etiology of the relatively high frequency of CCR5-32 in the european population is that it conferred resistance to the bubonic plaque in mid-14th century Europe

Selection at the ccr5 locus
Selection at the CCR5 locus

  • CCR532/CCR532 homozygotes are resistant to HIV and AIDS

  • The high frequency and wide distribution of the 32 allele suggest past selection by an unknown agent

The role of the chemokine receptor gene ccr5 and its allele del32 ccr5
The Role of the Chemokine Receptor Gene CCR5 and Its Allele (del32 CCR5)

  • Since the late 1970s

  • 8.4 million people worldwide

  • including 1.7 million children, have died of AIDS

  • an estimated 22 million people are infected with human immunodeficiency virus (HIV)

Ccr5 and its allele del32 ccr5
CCR5 and Its Allele ( del32 CCR5)

monocyte/macrophage (M),

T-cell line (Tl)

a circulating T-cell (T)

Mutations in multicellular organisms
Mutations In multicellular organisms

  • can be subdivided into:

    • Germline mutations

      • can be passed on to descendants

    • Somatic mutations

      • cannot be transmitted to descendants in animals

Germ somatic cell
Germ & Somatic cell

  • a mutation is present in a germ cell

    • can give rise to offspring that carries the mutation in all of its cells

    • Such mutations will be present in all descendants of this cell

    • This is the case in hereditary disease

  • a mutation can occur in a somatic cell of an organism

  • certain mutations can cause the cell to become malignant

    • cause cancer

Classification by effect on structure
ClassificationBy effect on structure

  • Gene mutations have varying effects on health:

    • where they occur

    • whether they alter the function of essential proteins

Point mutations
Point mutations

  • caused by chemicals/malfunction of DNA replication

  • exchange a single nucleotide for another

  • Most common is the transition that exchanges a purine for a purine (A ↔ G)

  • or a pyrimidine for a pyrimidine, (C ↔ T)


  • caused by:

    • Nitrous acid

      • base mispairing

    • 5-bromo-2-deoxyuridine (BrdU):

      • mutagenic base analogs

Base analog c t
base analog(C ↔ T)


  • Less common

  • exchanges a purine for a pyrimidine

  • or a pyrimidine for a purine (C/T ↔ A/G)

Point mutations that occur within the protein coding region of a gene
Point mutations that occur within the protein coding region of a gene

  • depending upon what the erroneous codon codes for:

    • Silent mutations:

      • which code for the same amino acid

    • Missense mutations :

      • which code for a different amino acid

    • Nonsense mutations :

      • which code for a stop and can truncate the protein


  • add one or more extra nucleotides into the DNA

    • usually caused by transposable elements

    • or errors during replication of repeating elements (e.g. AT repeats)

  • in the non/coding region of a gene may alter:

    • splicing of the mRNA (splice site mutation)

    • or cause a shift in the reading frame (frame shift)

      • significantly alter the gene product

  • Insertions can be reverted by excision of the Transposable element


  • remove one or more nucleotides from the DNA

  • Like insertions, these mutations can alter the reading frame of the gene

  • Deletions of large chromosomal regions, leading to loss of the genes within those regions

  • They are irreversible

Deletions insertions duplications

  • Out of frame

  • In frame

Deletions insertions duplications1

  • Out of frame:

    • result in frameshifts giving rise to stop codons.

    • no protein product or truncated protein product

    • deletions/insertions in DMD patients : truncated dystrophins of decreased stability

    • RB1 gene - usually no protein product in retinoblastoma

Deletions insertions duplications2

  • In frame:

    • loss or gain of amino acid(s)

    • depending on the size and may give rise to altered protein product with changed properties

    • eg CF Delta F508 loss of single amino acid

    • In some genes loss or gain of a single amino acid: mild

In frame
In frame:

  • In some regions of RB1 a single amino acid loss:

    • rise to mild retinoblastoma or incomplete penetrance

  • BMD patients:

    • Some times in-frame deletions/duplications

  • DMD deletions:

    • mostly disrupt the reading frame

Deletions insertions duplications3

  • In untranslated regions:

    • these might affect transcription/expression and/or stability of the message:

      • Fragile X

      • MD expansions

Amplifications gene duplications
Amplifications(gene duplications)

  • leading to multiple copies of all chromosomal regions

  • double-minute chromosomes:

    • Sometimes, so many copies of the amplified region are produced

    • they can actually form their own small pseudo-chromosomes

  • increasing the dosage of the genes

Chromosomal translocations
Chromosomal translocations:

  • Fusion genes:

    • Mutations: to juxtapose previously separate pieces of DNA

    • potentially bringing together separate genes to form functionally distinct (e.g. bcr-abl)

  • Chromosomal translocation:

    • interchange of genetic parts from nonhomologous chromosomes

Lethal mutations
Lethal mutations

  • lead to a phenotype:

    • incapable of effective reproduction

Interstitial deletions
Interstitial deletions:

  • an intra-chromosomal deletion:

    • removes a segment of DNA from a single chromosome

    • For example, cells isolated from a human astrocytoma, a type of brain tumor

    • have a chromosomal deletion removing sequences between the "fused in glioblastoma" (fig) gene and the receptor tyrosine kinase "ros", producing a fusion protein (FIG-ROS)

    • The abnormal FIG-ROS fusion protein has constitutively active kinase activity

    • causes oncogenic transformation (a transformation from normal cells to cancer cells)


  • a primary tumor of the central nervous system

  • develops from the large, star-shaped glial cells known as astrocytes

  • Most frequently astrocytomas occur in the brain

  • but occasionally they appear along the spinal cord

  • occur most often in middle-aged men

  • Symptoms of an astrocytoma, similar to other brain tumors:

    • depend on the precise location of the growth

    • For instance, if the frontal lobe is affected

      • mood swings and changes in personality may occur

      • a temporal lobe tumor is more typically associated with speech and coordination difficulties

AA: anaplastic astrocytomas(60.6%)

GBM: glioblastoma multiforme (65%)

  • Chromosomal inversions:

  • Reversing the orientation of a chromosomal segment

  • Loss of heterozygosity:

    • loss of one allele:

      • either by a deletion

      • recombination event

By effect on function
By effect on function

  • Loss-of-function mutations

  • Gain-of-function mutations

  • Dominant negative mutations

  • Lethal mutations

Loss of function mutations
Loss-of-function mutations

  • Wild type alleles typically encode a product necessary for a specific biological function

  • If a mutation occurs in that allele, the function for which it encodes is also lost

  • The degree to which the function is lost can vary

Loss of function mutations1
Loss-of-function mutations

  • gene product having less or no function:

    • Phenotypes associated with such mutations are most often recessive:

    • to produce the wild type phenotype!

      • Exceptions are when the organism is haploid

      • or when the reduced dosage of a normal gene product is not enough for a normal phenotype (haploinsufficiency)

Loss of function mutations2
Loss-of-function mutations

  • mutant allele will act as a dominant:

  • the wild type allele may not compensate for the loss-of-function allele

  • the phenotype of the heterozygote will be equal to that of the loss-of-function mutant (as homozygote)

    • to produce the mutant phenotype !

Loss of function mutations3
Loss-of-function mutations

  • Null allele:

    • When the allele has a complete loss of function

      • it is often called an amorphic mutation

  • Leaky mutations:

    • If some function may remain, but not at the level of the wild type allele

  • The degree to which the function is lost can vary

Gain of function mutations
Gain-of-function mutations

  • change the gene product such that it gains a new and abnormal function

  • These mutations usually have dominant phenotypes

  • Often called a neomorphic mutation (A* B)

*Normal allele

Gain of function mutations1
Gain-of-function mutations

  • Although it would be expected that most mutations would lead to a loss of function

  • A mutation in which dominance is caused by changing the specificity or expression pattern of a gene or gene product (Gain-of-function!), rather than simply by reducing or eliminating the normal activity of that gene or gene product

Dominant negative mutations
Dominant negative mutations

  • Dominant negative mutations:

    • antimorphic mutations (B A)

    • an altered gene product that acts antagonistically to the wild-type allele

    • These mutations usually result in an altered molecular function (often inactive):

      • Dominant

      • or semi-dominant phenotype

Dominant negative mutations1
Dominant negative mutations

  • In humans:

    • Marfan syndrome is an example of a dominant negative mutation

    • occurring in an autosomal dominant disease

    • the defective glycoprotein product of the fibrillin gene (FBN1):

      • antagonizes the product of the normal allele

Types of dominant mutation 10
Types of dominant mutation (10%)

  • Muller (1932) quantitative changes to a pre-existing WT character:

  • Amorph

  • Hypomorph

  • Hypermorph

  • Antimorph

  • neomorph


a/b globin

LDL Receptor

(Genetic mechanisms)

Null / leaky Allele

(Semi- and Dominant)


g globin



Collagen/ Fibrillin


Dominant negative mutations

in cis (hem S+ b23Val>Ile)

Gain-of-function mutations


Molecular and genetic classification of dominant mutation
Molecular and Genetic classification of dominant mutation

  • reduced gene dosage, expression, or protein activity (haploinsufficiency)

  • increased gene dosage

  • ectopic or temporally altered mRNA expression

  • increased or constitutive protein activity

  • dominant negative effects

  • altered structural proteins

  • toxic protein alterations

  • new protein functions

Reduced gene dosage expression or protein activity haploinsufficiency
Reduced gene dosage, expression, or protein activity (haploinsufficiency)

  • Inactivation of one of a pair of alleles

    • Mutation > loss of function:

      • Deletion, Ch Translocation, truncation,…

      • Type I collagen

      • globins

      • LDL-Receptor

    • Regulatory genes:

      • PAX3

Waardenburg syndrome pax3
Waardenburg Syndrome (haploinsufficiency) (PAX3)

  • Deafness

  • pigmentary anomalies

  • white forelock

  • heterochromia iridis

  • partial albinism

  • Prominent broad nasal root

  • Hypertrichosis of the medial part of the eyebrows

Heterochromia iridis
heterochromia iridis (haploinsufficiency)

Increased dosage
Increased Dosage (haploinsufficiency)

  • Increase gene dosage to three copies affect phenotype others, than reduction to one copy (+21, +18, +13, XXY, than X0,…)

  • Critical genes are important

  • PMP-22: duplication >Charcot-Marie-Tooth disease:

    • Haploinsufficient > different phenotype of Increased Dosage!

Increased dosage in charcot marie tooth disease
Increased Dosage in (haploinsufficiency) Charcot-Marie-Tooth disease:

Ectopic or temporally altered mrna expression
Ectopic or Temporally altered mRNA Expression (haploinsufficiency)

  • Point mutation in g, d, b

  • Alters binding of the transacting factor

    • Abrogate the normal switch from expression of :

      • g to d and b

Hpfh as a globin disease
HPFH (haploinsufficiency) as a δβ-globin Disease

  • Large deletions at the β-globin locus

  • from the region close to the human Aγ gene to well downstream of the human β-globin

  • gene and including deletion of the structural δ- and β-globin genes

HPFH (haploinsufficiency)

  • Heterozygotes:

    • a normal level of HbA2

    • even higher levels of HbF (15 to 30 %)

  • Homozygotes:

    • clinically normal

    • albeit with reduced MCV and MCH

  • Compound heterozygotes with b thalassemia:

    • clinically very mild

Why mutations of structural proteins are frequently dominant
Why mutations of structural proteins are frequently dominant?

  • Admixture of normal and abnormal structure components will disrupt the overall structure

  • Biochemical analysis:

    • Abnormal mRNA

    • Cellular processing

    • Secretion

    • Without mature Fibrills

      • Type I Collagen, Fibrillin in Marfan

Toxic protein alterations
Toxic protein alterations dominant?

  • Usually missense mutations:

    • Disrupt normal function

    • Lead to toxic products or precursors

  • Sickle cell mutations (hem S, b6Glu>Val)*

  • * Although : recessive

  • Coinheritance in cis (hem S+ b23Val>Ile)

    • Sickling to manifest in the heterozygote!

Toxic protein alterations1
Toxic protein alterations dominant?

  • Various point mutations in rhodopsin

    • Slow degeneration of rod photoreceptor outer segment

New protein functions
New protein functions dominant?

  • Creation of new , adventageus protein functions by mutation:

    • The life blood the evolution

    • Occurs over protracted time scale

    • Protein with truly new function: rare

    • Usually pathological

    • Juxtaposition of domains from different proteins.

      • Generate new function: ABL-BCR (9;22) Philadelphia translocation

A gene affecting brain size
A gene affecting brain size dominant?

Microcephaly (MCPH)

  • Small (~430 cc v ~1,400 cc) but otherwise ~normal brain, only mild mental retardation

  • MCPH5 shows Mendelian autosomal recessive inheritance



Bond et al. (2002) Nature Genet. 32, 316-320

Other mechanism
Other mechanism dominant?

  • Genomic imprinting:

  • If a gene is transcribed only from the ch originating from one of the two parents

  • The locus is hemizygous

  • Mutation of the allele on the active chromosome

    • Inactive the locus

  • Mutation of the other chromosome

    • No phenotypic effect

      • Beckwith-wiedermann syndrome

Beckwith wiedermann syndrome bws
Beckwith-wiedermann syndrome ( dominant?BWS)

  • The incidence of BWS :

    • 1:13700 live births

  • The increased risk of tumor formation in BWS patients:

    • 7.5%

The concepts of dominance recessive
The concepts of dominance & recessive majority (over 90%) of mutations are recessive to wild type

  • Formulated by Mendel (1965)

  • Why are some disease dominant and other recessive?

  • Dominance is not an intrinsic property of a gene or mutant allele

  • Relationship between the phenotypes of 3 genotypes (AA, AB, BB):

    • Dominant & Semi dominant (10%)

    • Recessive (90%)

Semi dominant
Semi dominant majority (over 90%) of mutations are recessive to wild type

  • Example of homozygous mutants:

    • Thalassemia, Familial hypercholesterolemia

    • Phenotype of the homozygote

      • More severity than heterozygote

  • Huntington:

    • True dominant to wild type

Dominant mutations are much rarer than recessive ones
Dominant mutations are much rarer than recessive ones majority (over 90%) of mutations are recessive to wild type

  • Insertional inactivation by retroviral DNA in mouse genom:

    • 10-20:1 (Rec:Dom)

  • Wright et al.:

    • Physiology of the gene action

  • Fisher et al.:

    • Accumulation of modifier alleles at other loci

Alga chlamydomonas
Alga majority (over 90%) of mutations are recessive to wild type Chlamydomonas

  • Usually haploid

  • In a diploid background

    • Nevertheless : recessive behavior

    • Supporting: Wright ‘s theory

  • Indeed, diploidy:

    • Protects against recessive mutations!

Why most inborn errors of metabolism are recessive
Why most inborn errors of metabolism are recessive? majority (over 90%) of mutations are recessive to wild type

  • Metabolic pathway:

    • Not critical rate limiting steps

    • Not qualitatively altered function

    • Perhaps: dominat mutations:

      • Developmental malformations

Recessive to dominant mutations
Recessive to Dominant mutations majority (over 90%) of mutations are recessive to wild type

  • Caenorhabditis elegans (C elegans):

  • Recessive mutations at a series of loci termed smg:

    • May alter the behavior of mutations from recessive to dominant

  • It seems: Wt smg: encode proteins :

    • Recognize and degrade mutant mRNA species (surveillance)