Download MCB Lecture 2 – Mutation and Disease Part 1

MCB Lecture 2 – Mutation and Disease Part 1
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What is a Polymorphism?
o A rare allele that exists at a frequency of 0.01 in a human population
What is the sequence that signals the splicing of Introns and Exons?
o GU-----AG
What are indels?
o Insertion/Deletion Mutations
When you have a Recessive Disorder, what kind of protein is usually
affected?
o Enzymes
o Transporters
When you have a Dominant Disorder, what kind of protein is usually
affected?
o Structural Proteins
o Transcription Factors
What is the Mode of Inheritance for Duchenne Muscular Dystrophy?
o X-Linked Recessive
What type of mutation does DMD have to be?
o Some kind of Null Mutation, because NO Dystrophin is produced.
Because DMD is a Null Mutation, what types of mutations could cause it?
o Deletions
o Frameshifts
o Nonesense Mutations
What is the Mode of Inheritance for Becker Muscular Dystrophy?
o X-Linked Recessive
What type of mutation causes Becker Muscular Dystrophy?
o In-Frame Deletion (Residual Function of Protein)
 Multuples of 3
AUTOSOMAL RECESSIVE DISEASES
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What is the Mode of Inheritance of ALL Amino Acid Metabolism Disorders?
o Autosomal Recessive
What is the Mode of Inheritance of Phenylketonuria (PKU)?
o Autosomal Recessive
What enzyme is defective in PKU? What does this cause molecularly?
o Phenylalanine Hydroxylase
o Phenylpyruvate builds up
What are the effects of PLU?
o Blue sclera, decreased IQ
o HYPERPHENYLALANEMIA
How can you treat PKU?
o A low-Phe diet
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Does PKU exhibit Locus Heterogeneity or Allelic Heterogeneity?
o Allelic Heterogeneity
o Different mutations in the same Phenylalanine Hydorxylase gene
cause the same phenotype of PKU
What is Hyperphenylalanemia? Mode of Inheritance?
o Autosomal Recessive
o Caused by high levels of Phenylalanine
Does Hyperphenylylanemia exhibit Locus Heterogeneity or Allelic
Heterogeneity?
o Locus Heterogeneity
What are the two ways a patient can have Hyperphenylylanemia?
o PKU
o BH4 Deficiency (Co-Factor)
What is the difference between patients with Hyperphenylylanemia from
PKU versus BH4 Deficiency?
o A low-Phe diet will help patients who have PKU, because there will be
less buildup of Phe in the system, preventing mental retardation.
o In patients with BH4 Deficiency, a low-Phe diet still causes Mental
Retardation because BH4 is a co-factor also required for
neurotransmitter synthesis.
What is the Mode of Inheritance for Alkaptonuria?
o Autosomal Recessive
What enzyme is deficient in Alkaptunuria?
o Homogentistic Acid Oxidase
What is the major symptom of a patient with Alkaptonuria?
o Following standing, the patient’s urine will turn black.
What is the Mode of Inheritance for Oculocutaneous Albinism?
o Autosomal Recessive
What is the enzyme that is deficient in Oculocutaneous Albinism?
o Tyrosinase Deficiency
o Inability to convert Tyrosine  Melanin
Is Oculocutaneous Albinism exhibiting Locus Heterogeneity or Allelic
Heterogeneity?
o Locus Heterogeneity
What is the Mode of Inheritance for Homocystinuria?
o Autosomal Recessive
What enzyme is deficient?
o Cystathionine B-Synthetase (CBS)
What is the Mode of Inheritance of Maple Syrup Disease?
o Autosomal Recessive
What enzyme is deficient in Maple Syrup Disease?
o Branches chain Ketoacid Decarboxylase
What is unique about the incidence of Maple Syrup Disease?
o Founder’s Effect causes a higher frequency in PA Mennonites.
HEMOGLOBINOPATHIES (AUTOSOMAL RECESSIVE)
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What is Embryonic Hemoglobin?
o ζ2, ε2
What is Fetal Hemoglobin?
o α2, γ2
What is Adult Hemoglobin?
o (HbA: α2, β2) & (HbA2: α2, δ2)
Which Hemoglobin Type can indicate B-Thalassemia if it is above 4% in
adults?
o HbA2
What is the name of the Enhancer that controls expression across the cluster
of Hemoglobin Genes?
o Locus Control Region (LCR)
THALASSEMIAS
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What are Thalassemia’s?
o Imbalances of Globin Chain Production  Accumulation of Free
Globin Chains in the RBC Precursors  Hemolysis of RBC 
Hemolytic Anemia with Hyperplasia of Bone Marrow
What type of mutation occurs in a-thalassemia?
o Deletion
What type of mutation occurs in B-thalassemia?
o Null Mutation
What is the Mode of Inheritance of a-thalassemia?
o Autosomal Recessive
What mutates in a-thalassemia?
o Deletion of a-globin due to unequal crossing over during Meiosis.
When the a-thalassemia is mutated, what is the consequence that causes the
pathology?
o B-thalassemia builds up the cell
What type of test can you perform to see the A-thalassemia deletion?
o Southern Blot
o Deletions will change distance between restriction sites
There are three levels of severity regarding A-thalassemia. What are they?
o Hydrops Foetalis
o Hb H
o Hb Constant Spring
What is Hydrops Foetalis (Hb Barts)?
o Most severe type of A-Thalassemia
o No a-globin synthesis at all.
o Lethal in utero
What is Hb H?
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o Milder than Hb Barts because there is some a-globin synthesis (25%)
o Majority of hemoglobin is a B-tetramer (unstable)
What is Hb Constant Spring?
o Phenotypically similar to Hb H
o Mutation of STOP CODON in a-globin leads to longer, unstable protein
o Protein is degraded, so there is no synthesis of normal a-globin
Given the following A-Thalassemia’s, how many function a-genes are
produced?
o Normal
 4
o Silent Carrier
 3
o Mild Carrier
 2
o Hb H
 1
o Hydrops Fetalis
 0
What is the Mode of Inheritance for B-Thalassemia?
o Autosomal Recessive
What is the mutation that causes B-Thalassemia?
o Null Mutation in B-Globin Gene (NO production of B-Globin)
What are some ways to test for B-Thalassemia?
o DNA Sequencing to determine the mutation
o ASO Panels to test if parents are carriers
Does B-Thalassemia exhibit Locus Heterogeneity or Allelic Heterogeneity?
o Allelic Heterogeneity
What are the three types of B-Thalassemia?
o B+-Thalassemia
o B0-Thalassemia
o Hb-Lepore
What is B+-Thalassemia?
o Trace B-Globin Synthesis causes Residual Function of enzyme and a
milder phenotype
o Posttranslational Defect
What is B0-Thalassemia?
o No B-Globin Synthesis
o Hair appearance of the skull
o Delection of the B-Globin Gene
What is Hb-Lepore?
o Unequal Crossing over
o Transcription of B-Globin is under the control of the δ--globin
promoter, so it is functionally equivalent to having none (null)
What is Hereditary Persistence of Fetal Hemoglobin?
o Deletion of β2 and δ2 removed promoter elements that LCR would
interact with so LCR continues to interact with γ (fetal hemoglobin).
o Exhibits normal phenotype unless patient is exposed to low levels of O2, because
fetal hemoglobin has a higher affinity for oxygen and will not release it.