Genetic Disorders Flashcards
Give an example of a nonconservative missense and a nonsense point mutation leading to disease respectively relating to the B-globulin chain of haemoglobin
- CTC (glutamic acid) -> CAC (valine) altering the B-globulin chain leading to sickle cell anaemia
- CAG (glutamine) -> UAG (stop) short B-globulin is rapidly degraded, resulting deficiency can give rise to a severe form of anaemia B0- thalassemia
What are two ways in which point mutations/deletions in noncoding sequences can lead to disease?
- If in promotor or enhancer regions could interfere with binding of transcription factors leading to a reduction or lack of transcription as in some thalassemias
- If in introns could lead to defective splicing of intervening sequences, interfering with normal processing of the initial mRNA resulting in failure to form mature mRNA.
Give an example of a 1) deletion of a multiple of three base pairs, 2) deletion resulting in a frameshift mutation, 3) insertion resulting in a frameshift mutation
1) The three base deletion in the common CF allele (lack of aa 508 (phenylalanine)
2) Single base deletion at the ABO (glycosyltransferase) locus leading to a frameshift mutation responsible for the O allele
3) Four base insertion in the hexosaminidase A gene, leading to a frameshift mutation (with a stop codon) that is a major cause of Tay-Sachs disease
What are alterations in protein-coding genes other than mutations?
Give an example
Structural variations like copy number changes - amplifications or deletions, or translocations.
E.g. translocation t(9;22) between BCR and ABL genes in chronic myeloid leukaemia (Philadelphia chromosome)
What are trinucleotide-repeat mutations?
Characterised by amplification of a sequence of three nucleotides. This is dynamic (degree of amplification increases during gametogenesis). Majority of affected sequences share G and C. Most lead to neurodegenerative disorders.
E.g. fragile X syndrome has 250-400 (average in normal populations is 29) repeats of CGG within the regulatory region of familial retardation 1 (FMR1) preventing normal expression.
What can mean that an autosomal dominant disorder is present, but is not expressed, or expressed differently to other individuals with the same disorder?
Variations in penetrance and expressivity respectively
Give an example of a disease resulting from an autosomal dominant loss of function mutation and a gain of function mutation:
Loss - Familial hypercholesterolemia (mutation of one gene leads to 50% loss in LDL receptors leading to elevation in cholesterol (the remaining ‘normal’ gene is unable to compensate))
Gain - Huntington disease (neo-protein huntingtin resulting from a trinucleotide repeat mutation in the Huntington gene)
What are four features that generally apply to most autosomal recessive disorders and distinguish them from autosomal dominant disease?
- Expression of defect tends to be more uniform
- Complete penetrance is common
- Onset frequently early in life
- Enzyme proteins are more frequently involved, as opposed to receptor or structural proteins
What is an example of an autosomal recessive disorder in each category of metabolic, hematopoietic and endocrine respectively?
Cystic fibrosis, sickle cell anaemia, congenital adrenal hyperplasia
What makes being heterozygous in an X-Linked recessive disorder different from being the same in an autosomal recessive disorder? (For females)
The random inactivation of one of the X chromosomes means females have a variable proportion of cells in which the mutant X chromosome is active. (Whereas both chromosomes are active in all autosomal pairs)
What are three examples of X-linked recessive disorders?
- Duchenne muscular dystrophy
- Haemophilia A and B
- Diabetes insipidus
What are three major consequences that could result from an enzyme defect?
- Accumulation of the substrate and/or intermediates. Increased concentration of some intermediate may also stimulate other minor pathways. High concentrations of any of these could be toxic.
- Decreased amount of end product that may be necessary for normal function. Also could lead to over production of intermediates and their catabolic products if end product is a feedback inhibitor
- Failure to inactivate a tissue-damaging substrate
Give an example each of a disease resulting from a single gene due to; 1. Defects in receptors and transport systems 2. Alterations in structure, function or quantity of nonenzyme proteins 3. Genetically determined adverse reactions to drugs
- Familial hypercholesterolemia
- Sickle cell disease
- G6PD deficiency (leads to severe haemolytic anaemia following some drugs e.g. primaquine)
What could be the biochemical and molecular basis of a single gene disorder?
- Consequences of enzyme defects
- Defects in receptors and transport systems
- Alterations in structure, function or quantity of non-enzyme proteins
- Genetically determined adverse reaction to drugs
What defect causes Marfan syndrome?
A defect in the extracellular glycoprotein fibrillin-1 (close to 1000 distinct mutations of the FBN1 gene on ch 15 have been found in individuals with Marfan syndrome, most are missense).
What are the two fundamental mechanisms by which loss of fibrillin leads to the clinical manifestations of Marfan syndrome?
- Fibrillin is the major component of microfibrils in the ECM, these provide a scaffold for tropoelastin to form elastic fibres. Microfibrils are particularly abundant in the aorta, ligaments and ciliary zonules that support the lens.
- Increased TGF-B bioavailability (normal microfibrils sequester TGF-B) leads to inflammation, deleterious effects on vascular smooth muscle development and increased metalloprotease activity (loss of ECM)
What are three morphological features Marfan syndrome can present with?
- Skeletal abnormalities e.g. long bones and joint ligament laxity
- Ocular changes e.g. bilateral subluxation or dislocation of the lens
- Cardiovascular lesions e.g. mitral valve prolapse and dilation of the ascending aorta due to cystic medionecrosis
What are the variants of Ehlers-Danlos syndrome all characterised by?
Defects in collagen synthesis or assembly
(including ECM molecules that influence synthesis indirectly e.g. tenascin-X a large multimeric protein that interacts with fibrillar type I, II and V collagens. Gene TNXB)
What clinical features could someone with an Ehlers-Danlos syndrome present with?
Fragile, hyperextensible skin vulnerable to trauma; hypermobile joints, ruptures involving the colon, cornea or large arteries. Wound healing is poor.
What is a syndrome that encompasses all three Mendelian patterns of inheritance?
The Ehlers-Danlos Syndromes
Of the EDSs Classic, Vascular, Kyphoscoliosis, Arthrochalasia and Dermatosparaxis which
1. Results from mutations in the PLOD1 gene encoding lysyl hydroxylase?
2. Is genetically heterogeneous and results from abnormalities in type III collagen?
3. Have the fundamental defect in the conversion of type I procollagen to collagen?
4. 90% of the time is related to mutations in genes for type V collagen (COL5A1 and COL5A2)?
5. Is caused by mutations in the ADAMTS2 gene that encodes procollagen-N-peptidase?
- Kyphoscoliosis
- Vascular
- Arthrochalasia and dermatosparaxis
- Classic
- Dermatosparaxis
As well as being used for membrane synthesis, steroid hormones and bile acids, what four homeostatic actions does free cholesterol in the cytoplasm have?
- Suppresses cholesterol synthesis by inhibiting the rate limiting enzyme 3-hydroxy-3-methlyglutaryl coenzyme A (HMG CoA)
- Activates acyl-coenzyme A:cholesterol acyltransferase (favouring esterification and storage)
- Suppresses synthesis of LDL receptors
- Upregulates PCSK9 expression (reduces recycling of LDL receptors and causes degradation of endocytosed receptors)
How does cholesterol enter the body from the diet?
Incorporated into chylomicrons in the intestinal mucosa and travel to blood via gut lymphatics. Chylomicrons hydrolysed by an endothelial lipoprotein lipase in capillaries of muscle and fat. The remnants are rich in cholesterol which then deliver to the liver. Some enters the metabolic pool and some is excreted as free cholesterol or bile acids into biliary tract.
How does VLDL (rich in triglycerides) end up as LDL (rich in cholesterol)?
VLDL secreted from liver into blood. Has apolipoproteins ApoB(B-100), ApoC and ApoE on the surface. In capillary endothelium of adipose tissue and muscle lipolysis of VLDL leads to IDL(VLDL remnant) with reduced content of triglycerides and increased cholesterol esters. ApoC is lost. 50% then taken up by LDL receptors (ApoB/E receptors) in liver and recycled to VLDL. The rest undergo further metabolic processing elsewhere removing most of the remaining triglycerides and ApoE resulting in ApoB carrying LDL particles
What are some cell types that posses high-affinity LDL receptors? And which clears 70% of plasma LDL
Hepatocytes, fibroblasts, lymphocytes, smooth muscle cells, adrenocortical cells
Liver clears approx 70%
What proteins are required for cholesterol to leave lysosomes?
NPC1 and NPC2
How do mutations in the LDLR gene (80-85% of cases), the gene encoding ApoB and an activating mutation in the PCSK9 gene lead to FH respectively?
- Reduced LDL receptors (heterozygotes 50%, homo 100%) ->increased plasma LDL, increased cellular synthesis of LDL, increased diversion of IDL to LDL (as uses same receptor)
- ApoB is the ligand for LDL receptors. Similar effect to above
- Greatly reduces number of LDL receptors on cell surface (because of increased degradation during recycling process). Similar effect to above
In hypercholesterolemia, what is responsible for the appearance of xanthomas and contributes to premature atherosclerosis?
The increased uptake of LDL by mononuclear phagocytes and possibly vascular walls through scavenger receptors
What to statins do?
Inhibit the enzyme HMG CoA and so suppressing intracellular synthesis of cholesterol leading to greater synthesis of LDL receptors
What are the consequences of a deficiency of a functional lysosomal enzyme?
- Incomplete catabolism of the substrate leading to accumulation within the lysosome (primary accumulation) and enlargement of the lysosome which as they become big and numerous enough can interfere with normal cell function.
- Reduced rate of processing of organelles in autophagy due to above accumulation
-persistence of damaged mitochondria which can trigger apoptosis and generate free radicals- secondary accumulation of autophagic substances including ubiquinated and aggregate-prone polypeptides such as a-synuclein and huntingtin protein
