SINGLE GENE DISORDERS Flashcards
what is an elctropherogram?
e
what are point mutations that cause disease?
Substitutions (missense)
Nonsense mutations
Insertion mutations
Deletion mutations
what mutation is sickle cell anaemia caused by?
β-globin gene
what is the β-globin gene lead to in sickle cell anaemia?
leads to a glutamic acid (E) being replaced by a valine (V) instead at position 6 in the protein
E6V
give an example of substitution (missense) mutation?
sickle cell anaemia
give an example of nonsense mutation?
Duchenne muscular dystrophy
what mutation is Duchenne muscular dystrophy caused by?
by nonsense mutations in dystrophin gene
what is the mutations in dystrophin gene cause in Duchenne muscular dystrophy?
Lysine (K) > unknown/unspecified (X) i.e. stop codon
K1524X
give an example of Insertion mutations?
Familial Hypercholesterolemia (FH)
what does Familial Hypercholesterolemia (FH) result in?
elevated levels of blood lipid
what mutation causes Familial Hypercholesterolemia (FH)?
mutation in exon 17 of the LDLR gene
c.2416_2417InsG
what does the c. stand for in the mutation codes?
cDNA
give an example of deletion mutation?
cystic fibrosis
what mutation causes cystic fibrosis?
deletion mutation that deletes the phenylalanine (F) residue at position 508 in the protein.
ΔUUU codon CFTR gene on chr. 7.
ΔF508
what does deletion mutation cause in the intron?
induces aberrant splicing of the DMD gene causing Duchene Muscular Dystrophy
what effect does Autosomal Dominant Inheritance have on characteristics?
Characteristic is manifested in the heterozygote of both sexes
is Autosomal Dominant Inheritance linked to a sex chromosome?
no
what is the chance of passing Autosomal Dominant Inheritance to offspring?
1 in 2
are homozygotes for Autosomal Dominant Inheritance rare?
are very rare and often have a more severe phenotype or show characteristic much earlier
what effect does homozygous for BMPR2 have?
embryonically lethal
what is Autosomal Dominant Inheritance?
both sexes affected and equally
likely to pass on the affected characteristic, e.g. PAH
what effect does Autosomal Recessive Inheritance have on characteristics?
Characteristic is not manifested in the heterozygote of both sexes
is Autosomal Recessive Inheritance linked to a sex chromosome?
no
is Autosomal Recessive Inheritance double defect?
yes
who does Autosomal Recessive Inheritance effect?
Affected individuals are born to unaffected parents
what is the chance of an affected parent passing on Autosomal Recessive Inheritance?
¼ as each parent has one WT allele and one mutant (affected) allele
what is Compound heterozygote?
refers to an affected individual with 2 different mutant alleles
what is true homozygotes?
Where an affected individual is from a consanguinous relationship then the 2 different mutant alleles will be the same
what are most classical genetic diseases?
autosomal recessive
what is Autosomal Recessive Inheritance?
both sexes affected.
The parents of the affected children in IV are both carriers
what do mutations responsible for recessive traits usually lead to?
Lack of gene expression
Lack of protein production
Production of a protein with reduced or absent function
what effect does X-linked Dominant Inheritance have on characteristics?
Characteristic is manifested in the heterozygote of both sexes
who is affected by X-linked Dominant Inheritance?
One parent is affected
There are significantly more affected females than males
what do females affected by X-linked Dominant Inheritance show?
typically show milder characteristics (and more variable expression) than males
what is the chance of a child being affected is this mother is affected by X-linked Dominant Inheritance?
1 in 2 chance
what is the effect of a male child having a father affected by X-linked Dominant Inheritance?
child will be unaffected (male child receives the Y chromosome from their father) but every daughter will be affected but show milder characteristics.
what effect does X-linked Recessive Inheritance have on characteristics?
Characteristic is not manifested in the heterozygote of both sexes
who are mostly affect by X-linked Recessive Inheritance?
males
Affected males are born to unaffected parents
No male- to male inheritance
what are the chances of sons and daughters being affected in X-linked Recessive Inheritance?
Sons -1 in 2 risk of being affected daughters -not affected they have a 1 in 2 risk of being a carrier.
what is manifesting heterozygotes?
Females through non-random mosaicism (X-chromosome inactivation) can show affects
can one gene cause different diseases?
yes more diseases attributed to mutations in single genes than genes mutated
what is Genetic Heterogeneity?
Different mutation in the same gene can lead to different diseases
what is Achondroplasia caused by?
by constitutively active –’Gain of function’ mutation
what mutation causes Achondroplasia?
Mutation in the fibroblast growth factor type 3 receptor leads to constitutive activity un-regulated by the receptor (FGFR3) function
what does FGFR3 do?
promotes differentiation of cartilage into bone
what does Gain-of-function mutation activate?
activates the receptor causing premature conversion of the growth plate into bone
can multiple genes cause one disease?
yes
give an example of when multiple genes cause one disease?
Xeroderma pigmentosum (XP)
how does Xeroderma pigmentosum (XP) occur?
Mutations in 8 different genes that all function in DNA-damage repair lead to XP (8 variants) / DNA replication
what other factors influence the phenotype of single gene disorders?
penetrance
expressivity
phenocopy
environmental effects
what is penetrance?
The frequency with which a person manifests the gene that they possess
do all dominant mutations display penetrance?
Not all display 100% penetrance
what is penetrance determined by?
genetic and environmental factors
what is expressivity?
Variation in the severity of the symptoms caused by a mutation
give an example of expressivity?
in sickle cell anaemia (which is always caused by the same mutation) symptoms range from very severe to extremely mild
what is phenocopy?
An environmental modification that mimics a genetic disease
give an example of phenocopy?
confusing genetic deafness with deafness caused by Rubella during pregnancy
give examples of environmental effects that influence the phenotype of single gene disorders?
phenylketonuria, a disease that once diagnosed is treatable via provision of a low phenylalanine diet
hypoxia many induce pulmonary arterial hypertension (PAH)
what types of tests are carried out?
Newborn screening Diagnostic testing Carrier testing (test for parents if carry one copy of mutation, that in 2 copies causes a disorder) Prenatal testing Preimplantation genetic diagnosis Predictive and presymptomatic testing
