ch 11 The Molecular Basis of Genetic Disease

Flashcards about the molecular basis of genetic disease.

Define Molecular Disease

Disorders caused by a change affecting a gene, its structure, and/or its expression, which changes the amount or function of the gene product.

Define Biochemical Genetics

The study of phenotype at the level of proteins, biochemistry, and metabolism.

Mutations can affect protein function. Define the 4 ways?

1. Loss of function mutation

2. Gain of function mutations

3. Novel property mutations

4. Mutations associated with heterochronic or ectopic gene expression

1. Loss of function mutation - no functional gene product at all

2. Gain of function mutations - too much gene product

3. Novel property mutations - specific type of missense causing protein to gain a new function or abnormal function

4. Mutations associated with heterochronic or ectopic gene expression

   1. heterochronic = time of gene expression is inappropriate

   2. Ectopic = gene is in the wrong place such as a specific tissue and the tissue is not supposed to express gene there (hair on eyes)

Describe loss of function mutations

• most common by far

• for protein coding

• severity of disease depends on how much function is lost

• ex: Alpha Thalassemia (deletion), Turner Syndrome, Retinoblastoma, Beta thalassemias (may affect RNA splicing)

Describe Gain of function mutations

• can increase production of a normal protein

  • Ex: Down Syndrome, 1 form of Familial Alzheimers, Charcot marie tooth disease type 1A

• Can enhance normal function of protein

  • ex: hemoglobin kempsey

• commonly due to gene dosage (duplication)

What is the result of mutations in the coding region of proteins?

Structurally abnormal proteins may lead to a loss or gain of function or novel property that causes disease.

What can mutations in regulatory elements alter?

Can alter the abundance of mRNA or the time or cell type in which the gene is expressed.

Give an example of a novel property mutation

Sickle cell disease; caused by an amino acid substitution that doesn't interfere with its ability to transport oxygen, but the new property is the polymerization that deforms the red blood cell.

Where do heterochronic and ectopic mutations take place?

Mutations in the regulatory regions of a gene.

What are the eight steps at which mutations can disrupt the production of a normal protein?

Transcription, translation, polypeptide folding, post-translational modification, assembly of monomers, subcellular localization, cofactor binding, and protein function.

What are the three genetic causes for variation in clinical phenotype observed in an inherited disease?

Allelic heterogeneity, locus heterogeneity, and the effect of modifier genes.

Allelic Heterogeneity vs Locus Heterogeneity

Allelic heterogenetiy - different mutations in the same gene cause the same disease (2 mutations > same disease)

Locus heterogeneity - mutations at different genes, cause same disease or phenotype (2 genes > same mutation)

______ is due to presence of multiple alleles at a single locus

allelic heterogeneity

Null Allele

A completely non-functional allele.

• form of allelic heterogeneity

Locus Heterogeneity

Mutations in more than one locus result in a specific condition.

ex: thalassemia

Effects of Modifier Genes

Variation in phenotype results from the effects of one gene on another.

• they do not cause the disease direclty but modify how mild or severe the condition appears

ex: beta-thalassemia homozygotes with alapha thalassemia variant

______ are the most common single-gene disorders

Hemoglobinopathies

• ex: normal adult hemoglobin (Hb A)

Describe the structure of a Normal Adult Hemoglobin (Hb A)

Two α-globin and two beta-globin peptides

There are 5 other normal Hbg (compared to Hb A) and they are made up of ______ and ______.

• Which one is located on chromosome 16?

• Which one is found on chromosome 11?

2 alpha like chains and 2 non-alpha like chains

• Genes for the alpha and alpha-like chains (2 identical alpha genes)

• Beta and beta-like globlin (globulin is a type of protein that binds oxygen

Define Globin Switching

Process of expression of various globin genes change during development (occurs in alpha and beta)

• Hgb F (in beta family) predominate during fetal life but by 3 months age, child has almost all Hb A

The locus of the locus control region plays an epigenetic role, how?

Creates an open chromatin configuration allowing transcription factors access to regulatory elements

Active Chromatin Hub

Beta-Globin Locus Control Region (LCR)

Each of the five regions of open chromatin contains several consensus binding sites for both erythroid-specific and ubiquitous transcription factors.

Clinical Significance of the LCR

1. Failure to express the genes of the beta-globin cluster. 2. Likely an Important target for gene therapy in related diseases. 3. Understanding the molecular mechanism of globin switching may allow increased expression of gamma-globin for beta-thalassemia.

Mechanism of Sickle Cell Disease

Polymerization of deoxygenated sickle hemoglobin (HbS), resulting in a deformity of the red blood cell and a marked decrease in its ability to pass through the microvasculature.

Modifier Genes and Sickle Cell Disease

Higher levels of Hgb F (2 alpha, 2 gamma) create less severe disease because Hgb F is an effective 02 carrier and inhibits polymer formation of Hgb S.

Variants with Altered Oxygen Transport

Oxygen binding and release is impaired, but other properties generally remain intact, with minimal effect on Hgb stability.

Hb Kempsey

The mutation locks the Hgb into the high-affinity state, so it won't release the 02 to the tissues, resulting in polycythemia.

What is the Pathophysiological Effect of Hb Hammersmith

An unstable Hb leading to Hb precipitation and hemolysis and also low oxygen affinity.

What is the Pathophysiological Effect of Hb Hyde Park

The substitution makes oxidized heme iron resistant to methemoglobin reductase, cyanosis (asymptomatic).

Thalassemia

Cause by a reduction in the synthesis/stability of alpha or beta globin chains with the excess chains precipitate and damage the RBC membrane, causing hemolysis.

Alpha-Thalassemias

Reduction in the synthesis/stability of alpha globin chains.

Beta-Thalassemias

Reduction in the synthesis/stability of beta globin chains.