Mutation with transmission pattern of single gene disorder

MUTATION WITH TRANSMISSION
PATTERN OF SINGLE GENE
DISORDER
Speaker-
Dr.H.S.Sarkar

What are GENES!
 Cells----Nucleus---Chromosome---DNA-- Genes

A gene is the basic physical and functional unit of heredity. It is a
section of the DNA that codes for one specific protein. In humans,
genes vary in size from a few hundred DNA bases to more than 2
million bases. The Human Genome Project has estimated that
humans have about 20,000 protein encoding genes,which is about
1.5% of the genome.
Continue…
Every person has two copies of each gene, one inherited from each
parent. Most genes are the same in all people, but a small number of
genes (less than 1%of the total) are slightly different between
people.

Some Terminologies
 GENOTYPE - An individual’s genetic constitution.
 PHENOTYPE - Observable expression of genotype as a trait
(morphological, clinical, biochemical, or molecular) or disease.
 LOCUS-It is the position of a gene in a chromosome.
 ALLELE- is the variant form of a given gene (one member of a pair)
that is located at a specific position on a specific chromosome. An
individual inherits two alleles for each gene, one from each parent.
 WILD-TYPE (NORMAL) ALLELE: prevailing version, present in
majority of individuals.
 MUTANT ALLELE: usually rare, differ from wild-type allele by
mutation.
 MUTATION: permanent change in nucleotide sequence or
arrangement of DNA.

Continued..
•HOMOZYGOUS - Having two identical alleles at a
particular locus, usually in reference to two normal alleles or
two disease alleles.
•HETEROZYGOUS - Having two different alleles at a
particular locus, usually in reference to one normal allele
and one disease allele.
•DOMINANT TRAIT - a trait that is expressed in a
heterozygous state.
•RECESSIVE TRAIT - a trait that is hidden in a
heterozygous state.
•CODON-A sequence of three adjacent nucleotides on a
strand of a nucleic acid (such as DNA) that constitutes the
genetic code for a specific amino acid that is to be added to
a polypeptide chain during protein synthesis.

Mutations..
Mutations are defined as permanent change in the DNA.
Mutations that arise in the germ cells are transmitted to the progeny and
give rise to inherited diseases.
Mutations that arise in somatic cells do not cause hereditary diseases but
are important in the genesis of cancers and some congenital
malformations.
GENERAL PRINCIPLES OF GENE MUTATIONS;
1)Point Mutations within coding sequences – A single base is
substituted with a different base. It may alter the code in a triplet of
bases and lead to the replacement of one amino acid by another in a
gene product.
For example in Sickle cell anemia – Nucleotide triplet CTC--CAC
(GAG—GUG in mRNA).
This results in substitutions of Glutamic acid –to- Valine.
This single amino acid substitutions alters the physiochemical properties of
the haemoglobin which results in sickling of RBC’s in deoxygenated
state. This is an example of MISSENSE mutation since the mutation
alters the meaning of the sequence of the encoded protein.

Continued..
Also a point mutation may change an amino acid codon to a chain
terminator or stop codon which is then known as a nonsense
mutation.For example
In a Beta-globin chain of a haemoglobin,
A point mutation CAG—UAG results in premature
termination of Beta globin gene translation---short peptides
produced ---rapidly degraded---deficiency of Beta globin
chains---Thalassemia.
2)Mutations within non coding sequences-Transcription of DNA is
initiated and regulated by promoter and enhancer sequences-
binding sites for transcription factors in the NON CODING portion of
the DNA.
Point mutations or deletions involving these regulatory sequences may
interfere with binding of transcription factors and thus lead to a
marked reduction in or total lack of transcription.
Also point mutation in introns resulting in defective splicing and
consequently failure to form mature mRNA and the gene product is
not synthesized.
UAA
UAG
UGA

CONTINUED…
 Intron 1position 5(G-C)
 619 base pair deletion
 Intron 1 position (G-T)
The above point mutations and deletions are some of the common
beta thalassemia mutations involving non coding sequences in India.
3)Deletions and Insertions-involving coding sequences can have two
possible effects on the encoded protein .
a)If number of base pair involed is 3 or multiple of 3 the reading
frame will be intact ---protein lacking or gaining one or more amino
acid synthesized.
Ile - Ile – Phe -Gly - Val
Normal DNA…T ATC ATC TTT GGT GTT ….
CF DNA ….. T ATC AT_ _ _T GGT GTT….
Ile Ile Gly Val
Three-base deletion in the common cystic fibrosis (CF) allele results in
synthesis of a protein that lacks amino acid 508 (phenylalanine)

Continued..
b) If the number of affected coding bases is not a multuple of 3 ----
alteration in reading frame of DNA strand ---FRAMESHIFT mutation-
---resulting in incorporation of a variable number of incorrect amino
acid followed by truncation resulting from a premature stop codon.
Arg Ile Ser Tyr Gly Pro Asp
Normal HEXA Allele…CGT ATA TCC TAT GCC CCT GAC….
Tay-Sachs allele ...CGT ATA TCT ATC CTA TGC CCC TGA
C…
Arg Ile Ser Ile Leu Cys Pro STOP
altered reading frame
Four-base insertion in the hexosaminidase A gene, leading to a
frameshift mutation. This mutation is the major cause of Tay-Sachs
disease.
4) Trinucleotide – repeat mutations- These mutations are
characterised by amplifications of a sequence of 3 nucleotides.eg.
Fragile X syndrome where there are 250-4000 tandem repeats of
sequence CGG within a gene called familial mental retardation
1(FMR 1) .

To summarise
Mutations can interfere with gene expressions at various
levels.
Transcription may be suppresed or altered by gene deletions, point
mutations, insertions, trinucleotide repeats involving coding or
noncoding portions of DNA ultimately resulting in change in gene
expression.

The Genetic Disorders:
Against this background we now turn our attention to 3
major categories of genetic disorders
1)Disorders related to mutation in single genes with large effects.
2) Chromosomal disorders : Defect is due to an excess or a deficiency
in whole chromsomes or chromsome segments (trisomy 21,Turner
syndrome, Klinefelter syndrome)
3) Complex multigenic disoders :Caused by interaction between
multiple variant forms of genes and environmental factors.Such
variations in genes are common within populations and are called
polymorphism.Some of the common diseases in this category
include atherosclerosis, diabetes mellitus, hypertension.

Single Gene Disorders(Mendelian
Disorders)
Gregor Mendel (1822 –1884)
conducted research on heritable traits
in pea plants.
Sir Mendel’s studies of inheritence pattern in pea plant represent a
solid foundation for our current understanding of single gene disorders
in humans.
When a certain gene can be pin pointed as a cause of disease we
refer to it as a single gene genetic disorder or a Mendelian disorder.

Transmission Patterns of Single Gene
Disorders
 Mendelian
• Autosomal Dominant
• Autosomal Recessive
• X-linked Recessive
• X-linked Dominant
• Y-linked
 Non-Mendelian
• Genomic Imprinting
• Trinucleotide repeats
• Mutations in
Mitochondrial genes
• Gonadal mosaicism

Transmission Patterns of Single Gene
Disorders
(Mendelian inheritence)
Patterns of Single Gene Inheritance depend on 2 factors:
1. Whether the gene is on an Autosome or a Sex chromosome
2. Whether the phenotype is Dominant or Recessive
Thus, there are 4 basic patterns of single gene inheritance
1. Autosomal Recessive
2. Autosomal Dominant
3. X-linked Recessive
4. X-linked Dominant
Y-linked disorders are exceedingly rare but the most
well-known examples typically cause
infertility. Only men have a Y chromosome and
so the Y is only passed from father to son.

Autosomal Dominant DisordersGenotype and phenotype correlation with gene locus for an
autosomal dominant trait
A a
Dominant allele Recessive allele
Genotype:
Phenotype:
Homozygous Heterozygous Homozygous
unaffectedaffected
Phenotype expressed in both homozygotes and heterozygotes for a mutant

Autosomal Dominant Disorders
 Autosomal dominant disorders are manifested in the
heterozygous state, so atleast one parent of an index case is
usually afffected.
 Both males and females are affected.
 Both can transmit.
 When affected person marries an unaffected one every child
has a 50% chance of being affected.
 Some patient do not have affected parents, such patient owe
their disorder to new mutation in either the egg or sperm from
which they were derived.
 Clinical features can be modified by variation in penetrance
and expressivity .

 Penetrance :
Penetrance refers to the proportion of people
with a particular genetic change (such as a mutation in a
specific gene) who exhibit signs and symptoms of a genetic
disorder. If some people with the mutation do not develop
features of the disorder, the condition is said to have reduced
(or incomplete) penetrance. Reduced penetrance often
occurs with familial cancer syndromes.
For example, many people with a mutation in
the BRCA1 or BRCA2 gene will develop cancer during their
lifetime, but some people will not. Doctors cannot predict
which people with these mutations will develop cancer or
when the tumors will develop.

Expressivity: If a trait is seen in all individuals carrying the
mutant gene but is expressed differently among individuals, the
phenomenon is called variable expressivity. e.g in
Neurofibromatosis type 1 manifestations range from
a) Brownish spot on the skin.
b) Multiple skin tumors.
c) Skelital diformities.

 Biochemical Mechanisms:
Most mutations lead to
a) reduced production of gene product.
b) dysfunctional or inactive protein
synthesis.
 Few other characteristics:
a)Enzyme proteins not usually of autosomal
dominant inheritance --- Hetorozygous usually normal--- 50%
reduction in enzyme activity can be compensated by
compensatory mechanisms.
b) protein involved in complex metabolic
pathways that are subject to feedback inhibition e.g In
Familial hypercholesterolemia, membrane receptor of LDL---
50% loss ---results in elevated cholesterol –predisposes to
atherosclerosis in affected heterozygotes.

c) Structural protein like collagen, RBC cytoskeleton (spectrin)—50%
reduction in the amounts of such proteins result in abnormal
phenotype.
d Even with a single mutant collagen chain, normal collagen trimers
cannot be formed, and hence there is a marked deficiency of
collagen. In this instance the mutant allele is called dominant
negative, because it impairs the function of a normal allele.
This effect is illustrated by some forms of osteogenesis
imperfecta, characterized by marked deficiency of collagen and
severe skeletal abnormalities.
e)Gain of function mutation: Less commonly mutant protein product
gains properties not shown by Wild-type protein.e.g Huntington’s
disease-abnormal protein(huntingtin)--- toxic to neurons ---hence
even heterozygous affected.

Genotype and phenotype correlation with gene locus
for an autosomal recessive trait
Autosomal Recessive Disorders
A a
Dominant allele Recessive allele
Genotype:
Phenotype:
Homozygous
unaffected
Heterozygous
unaffected
Homozygous
affected

Typical pattern is two heterozygous unaffected(carrier) parent.

Carrier couples has I in 4 chance of having an affected
offspring
Single largest category of Mendelian Disorders.
They occur when both alleles are mutated--Homozygous
state.
Both sexes affected equally.

If the mutant gene occurs with low frequency in the population,there is
a strong likelihood that the affected individual is the product of a
cosanguinous marriage.

 The expression of the defect tends to be more uniform than in
autosomal dominant disorder.
 Complete penetrance is common.
 Onset is frequently early in life.
 New mutations largely undetected because of asymptomatic
heterozygotes ----many generations pass before descendant of such
a person mate with other heterozygote.
 Autosomal recessive disorders include almost all in born error of
metabolism.
 While autosomal dominent disorder encode for the structural protein
here many mutated genes encode for enzymes.
 Usually due to mutations that reduce or eliminate the function of the
gene product (loss-of-function)
 In many cases: mutations that impair or eliminate the function of an
enzyme

GALACTOSEMIA(Classic Variant): There is a total lack of galactose-1-
phosphate uridyl transferase (also known as GALT).This due to
mutation of GALT Gene Cytogenetic Location: 9p13.3.
Results in accumulation of a)Galactose-1-phosphate(substrate)&
b)Galactitol and Galactonate(products of alternate
pathway)
Liver shows extensive fatty change and delicate

Sex-linked disorders
 All sex linked disorders are X-linked’
 Almost all are recessive.
 Several genes located in the “male –specific region of Y “ are
related to spermatogenesis. Males with mutations affecting Y linked
genes are usually infertile and hence there is no Y linked
inheritence.
 There are only a few X linked dominant conditions.
a) These disorders transmitted by an affected heterozygous
female to half her sons and half her daughter.
b) Affected father does not transmit to son but to all his
daughters.
Example-Vitamin D resistant rickets.

X-Linked Disorder
Male
Female
unaffected affected
Homozygous(wild type) Heterozygous Homozygous Mutant

X-Linked recessive Disorder
 These type of inheritance account for small number of well defined
clinical condition.
 Most part of Y is not homologous to X and so male is called
HEMIZYGOUS for X linked mutant gene.
 Affected male-- sons unaffected,---all daughters carrier.
 Sons of heterozygous woman 50% chance of getting the mutant
gene and being affected.

 Affects mainly males
 Affected males are usually born to unaffected parents
 Females may be affected if the father is affected and the mother is a
carrier, or occasionally as a result of nonrandom X-inactivation.
 Because of random inactivation of one of the X
chromosome in the female,a female has a variable proportion of
cells in which the mutant X chromosome is active .So there is a
possibility that the normal allele to be inactivated in the most cells
permitting full expression of heterozygous X-linked condition in the
female.
 Commonly normal allele is inactivated in only some of the
cell and thus heterozygous female express disorder only partially.
 For example in G6PD Deficiency ;- Haemolysis occurs in patients
when subjected to oxidant stress. In females a proportion of RBC
may be derived from precursors with inactivation of the normal
allele. Such red cells are at risk of haemolysis. Here, the female is
not just the carrier of this trait but also succeptable to oxidant stress
induced haemolytic reaction. Those severity is always less than in
hemizygous male or homozygous female.

Mutations in the G6PD gene reduce the amount of glucose-6-phosphate
dehydrogenase or alter its structure. As a result, reactive oxygen species can
accumulate and damage red blood cells. Factors such as infections, certain
drugs, or ingesting fava beans can increase the levels of reactive oxygen
species, causing red blood cells to be destroyed faster than the body can
replace them.
Inset, Red cells with
precipitates of denatured globin (Heinz
bodies) revealed by supravital staining.
As the splenic macrophages pluck out
these inclusions, “bite cells” like
the one in this smear are produced.

Biochemical and Molecular basis
of Single- Gene Disorders
Mendelian disorder result from alteration involving single gene.The
genetic defect may lead to formation of an abnormal protein or a
reduction in the output of the gene product.
Mechanisms involved are of 4 main categories:
1). Enzyme defects and their consequences – Mainly autosomal
recessive disorders.
2). Defects in receptor and transport system – For example familial
hypercholesterolemia.
3). Alteration in structure, function and quantity of nonenzyme proteins.
– mainly autosomal dominant disorders.
4).Mutation resulting in unusual reactions to drug. For Example G6PD
deficiency .

Single Gene Disorders with Non
Classic Inheritance
This group of disorders can be classified into 4 categories
 Diseases caused by trinuceotide- repeat mutations.
 Disorders caused by mutation caused by mitochondrial
genes.
 Disorders associated with genomic imprinting.
 Disorders associated with gonadal mosaicism

Single Gene Disorders with Non Classic
Inheritance
Trinucleotide – repeat mutations
Expansion of trinucleotide repeats is an important genetic cause of
human disease , particularly neurodegenerative disorders.
the copy number of repeats may have a significant effect on phenotype once a
certain number of repeat sequence is present (Huntington Disease, Fragile-X,
Myotonic dystrophy)

Single Gene Disorders with Non Classic Inheritance
FRAGILE X PEDIGREE:
Note that in first generation all sons are normal,all female carrier.During oogenesis in the
carrier female premutation expands to full mutation,and hence next generation all males
who inherit the X with full mutation are affected.
Features of fragile X syndrome worsen with each successive generation, as if the
mutation becomes increasingly deleterious as it is transmitted from a man to his
grandsons.This is reffered to as ANTICIPATION.

continue…
Expanded CGG segment turns off (silences) the FMR1 gene(Familial
Mental Retardation gene), which prevents the gene from producing
FMRP. Loss or a shortage (deficiency) of this protein disrupts
nervous system functions and leads to the signs and symptoms
of fragile X syndrome.

Inheritance
Mutation in Mitochondrial Genes
A feature unique to mtDNA is maternal inheritance since ova contain
numerous mitochondria where spermatozoa contain few therefore mtDNA
complement of the zygote is derived entirely from ovum.
Therefore all progeny of an affected male are normal but all children male
or female of the affected female manifest disease.
Below is a pedigree of Leber hereditary optic neuropathy,a disorder
caused by mutation in mitochondrail DNA.

Inheritance
Mutation in Mitochondrial Genes
 Because mtDNA encodes enzymes involved in oxidative
phosphorylation, mutations affecting these genes exert their
deleterious effects primarily on the organs most dependent on
oxidative phosphorylation such as the central nervous system,
skeletal muscle, cardiac muscle, liver, and kidneys.
 During cell division, mitochondria and their contained DNA are
randomly distributed to the daughter cells. Thus, when a cell
containing normal and mutant mtDNA divides, the proportion of the
normal and mutant mtDNA in daughter cells is extremely
variable.Therefore, the expression of disorders resulting from
mutations in mtDNA is quite variable.
 Example:In Leber hereditary optic neuropathy
Blurring and clouding of vision are usually the first symptoms .
These vision problems may begin in one eye or simultaneously in
both eyes;

Inheritance
Genomic Imprinting
Imprinting involves transcriptional
silencing of the paternal or maternal copies
of certain genes during gametogenesis.
For such genes only one functional
copy exist. Loss of the functional (not
imprinted) allele by deletion gives rise to the
disease.
In Prader-Willi deletion of q12 on
paternal chromosome 15 occurs genes in
this region of maternal chromosome are
imprinted so there is complete loss of
function resulting in mental retardation,
short stature, hypotonia,
hyperphagia,hypogonadism etc.
In Angelman deletion of the same region
from the maternal chromosome result in
mental retardation, ataxia, seizures and
inapproprate laughter. Here corresponding

Genomic Imprinting
Angelman Syndrome
Composite photograph of facial appearances of individuals with genetically

Inheritance
Genomic Mosaicism
 Genomic mosaicism result from mutation that occur postzygotically
during early embryonic development.
 If the mutation affects only cells destined to form the gonads, the
gametes carry the mutation but the somatic cell of the individual are
completely normal.
 Hence, a phenotypically normal parent who has gonadal mosaicism
can transmit the diseases causing mutation to the offsprings through
their mutated gametes.
 In some autosomal dominant disorders exemplified by osteigenesis
imperfecta, phenotypically normal parents have more than one
affected child. This is contrary to laws of Mendelian
inheritance.Gonadal mosaicism may be responsible for such
unusual pedigree.

Mosaicism
Mixed makeup: Mosaic expression of the
genes that code for coat color leads to the
characteristic patterns seen in calico cats.

Mutation with transmission pattern of single gene disorder

Mutation with transmission pattern of single gene disorder

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