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Robbins Path CH5

Robbins Pathology Chapter 5 Genetic Disorders

QuestionAnswer
exon a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA (introns) have been removed
intron nucleotide sequence within a gene that is removed by RNA splicing
Point mutation that leads to an inappropriate "stop" nonsense mutation
point mutation that subs in a "pretty close" AA conservative missense mutation
point mutation that swaps in an aa which causes significant protein change nonconservative missense mutation
change in the number of nucleotides frameshift. multiple of three can be okay, otherwise it will lead to a missense or nonsense mutation
miRNA function? micro RNA act to stop protein transcription
penetrance proportion of individuals with the mutation who exhibit clinical symptoms
how many genes do we have 20-30K (similar to small animals). Can be used to make ~100K proteins
Familial hypercholesterolemia is caused by a loss of function mutation in the LDL receptor
hereditary spherocytosis results from a loss of function mutation involving a key structural protein (alpha-spectrin) that forms the normal cytoskeleton elements of the red cell membrane. Causes RBCs to get grabbed by spleen
mutant allele in hereditary spherocytosis is classified as a ___________ _________. What does this mean? dominant negative (aka antimorph) which are dominant mutations that act in opposition to normal gene activity
what does 'dominant negative' mean? dominant mutation that acts in opposition to normal gene activity
what kind of gene mutation is involved in huntington's chorea? autosomol dominant, delayed expression, gain of function
Incomplete penetrance and variable expressivity are phenomena associated only with autosomal ______ inheritance Incomplete penetrance and variable expressivity are phenomena associated only with dominant inheritance
wilson disease autosomol recessive. accumulation of toxic copper in liver/tissues/eyes (Kayser fleisher rings).
which is more common x-linked recessive or dominant? x-linked recessive are more common (most common disease type in humuns)
mosaicism results because of x-inactivation (variable expression….. Penetrance)
what causes porphyria? single-gene enzyme defects. Caused by defect in enzyme in production of heme
achondroplasia. What causes? What happens? mutation in Fibroblast growth factor receptor (FGFR). Abnormal development of cartilage in the long bones.
thalassemia inherited autosomal recessive disease which results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin
ehlers-danlos syndromes genetic defect in the synthesis or structure of fibrillar collagen
most clinically significant type of ehlers-danlos? vascular type. They can have spontaneous rupture of arteries or bowel
cause of vitamin d-resistant rickets? Vitamin D receptor (VDR) is mutated such that it has complete or partial loss of function. Causes hypocalcemia and rickets. Most common in middle east
lysosomal storage disease group of diseases with multiple types. All effect lysosomal trafficing.
MPS mucopolysaccharidoses. Rare autosomal recessive lysosomal storage disease affects multiple organs/tissues. Not enough or nonfuctioning enzymes for breakdown of Glycosaminoglycans.
Hurler's Syndrome MPS 1
definition of Complex multigenic disorder occur when many polymorphisms, each with a modest effect and low penetrance are inherited.
polymorphism a genetic variant that has at least 2 alleles and occurs in at least 1% of the population
chromosomal disorders change in number or structure of one or more chromosome
causes of aneuploidy nondisjunction & anaphase lag
anaphase lag can happen during mitosis or meiosis. Chromomes fail to separate
Familial hypercholesterolemia is caused by a single gene mutation in LDL receptor (19p)
gaucher disease recessive mutation of glucocerebrosidase which cause an accumulation of glucocerebroside (usually in WBCs).
gaucher disease. describe Type I. Type I is non-neural with onset in childhood or early adult.
turner syndrome monosomy x. susceptible to coarctation of the aorta and bicuspid aortic valve.
xanthoma They are cutaneous manifestations of lipidosis in which there is an accumulation of lipids in large foam cells within the skin
corneal arcus white or gray ring around the cornea. Caused by hypercholesterolemia
what tell-tale cells do you see in xanthomas? (microscopically) foamy macrophages and cholesterol crystals
what pattern of inheritance is in familial hypercholesterolemia? autosomal dominant
how come macrophages can ingest LDL in soft tissues? macrophages have scavenger LDL receptors. Different than the messed up LDL receptor
most common causes of chronic hepatic fibrosis? infection (hep-c), alcohol abuse, non-alcoholic steatohepatitis associated with metabolic syndrome, Autoimmune disease
varices dialated veins (usually people mean esophageal varices)
why does hepatic fibrosis cause esophageal varices? fibrosis causes blood to back up in portal vein which puts increased pressure on veins in stomach and esophagus
sclerotherapy forcing clots in esophageal varices (endoscopic)
what color is cytoplasm in foamy macrophages? clear
inheritance of gaucher disease? autosomal recessive
number one symptom of gaucher disease? hepatosplenomegaly (followed by bone lesions, gaucher cells, many others)
type A aortic dissection? dissection that is very high on aorta
What is problem in Loeys-Dietz syndrome? a recently-discovered autosomal dominant genetic syndrome which has many features similar to Marfan syndrome, but which is caused by mutations in the genes encoding TGF-beta receptor
cardio vascular changes in monosomy X Turner syndrome has CV anomolies in 20-30% of cases. 10% coarctation of aorta. 16% have bicuspid aortic valve (has association with aortic wall abnormalities). Aortic stenosis
what is dr gryzbicki's favorite tumor in the whole wide world? teratoma (neoplasms composed of disorganized tissues from germ cell layers)
kleinfelter cause? multiple x chromosomes.
kleinfelter is at increased risk of? breast cancer, extragonadal germ cell tumors, autoimmune diseases
what percent of the human genome encodes proteins? less than 2%
two most common forms of DNA variations in the human genome? - single nucleotide polymorphisms - copy number variations
CNV copy number variations are structural rearrangements of the genome such as deletions, duplications, inversions, and translocations
epigenetics heritable changes in gene expression that are not caused by alterations in DNA sequence
explain activation of miRNA? (looking for two key enzyme names) - pre-miRNA is exported to cytoplasm - Dicer "cuts" it into miRNA (still double stranded) - miRNA separates (to single strand) - miRNA joins RISC (RNA induced silencing complex) - RISC complex cuts or blocks mRNA
difference between miRNA and siRNA? siRNA is introduced into the cell whereas miRNA come from nucleus. Both need Dicer/RISC
estimated 50% of spontaneous abortuses are because of? chromosomal abnormality
What is meant by "Mendelian disorder" disorder where there is a single gene mutation and a high penetrance
what kind of mutation is involved in sickle cell anemia? nonconservative missense mutation. A single amino acid substitution affects the beta-globin chain of hemoglobin. CAC to CDC (glutamic acid to valine)
beta0-thalassemia CAG to UAG (glutamic acid to stop codon) on beta-globin causes premature termination of beta-globin which is degraded. Severe anemia
Almost all trinucleotide-repeat mutations involve what nucleotides? C and G
mutations at several genetic loci that produce the same trait genetic heterogeneity
a single gene that leads to many end effects pleiotropism
give an example of a pleiotropic disease sickle cell disease. One gene mutation causes the primary sickeling, but also splenic, organ and bone problems
what is the term used to explain the range of problems that can occur in neurofibromatosis type 1? variable expressivity
why don't mutations in genes that encode enzymes manifest in autosomal dominant patterns? because there are two copies of the gene for the enzyme (one on each chromosome). You'd still get half (enough) of the enzyme
what kind of (non-enzyme) proteins are affected in autosomal dominant disorders? 1. those involved in regulation of metabolic pathways (example: LDL receptor in familial hypercholesterolemia) 2. structural proteins
example of gain of function disease? Huntington Disease. the trinucleotide repeatmutation gives rise to an abnormal protein (huntingtin) that is toxic to neurons. This explains why even heterozygotes are affected
Huntington disease (Autosomal dominant or recessive?) Autosomal dominant
Neurofibromatosis (Autosomal dominant or recessive?) Autosomal dominant
Myotonic dystrophy (Autosomal dominant or recessive?) Autosomal dominant
Tuberous sclerosis (Autosomal dominant or recessive?) Autosomal dominant
Polycystic kidney disease (Autosomal dominant or recessive?) Autosomal dominant
Familial polyposis coli (Autosomal dominant or recessive?) Autosomal dominant
Phenylketonuria (Affected protein type / protein name / Molecular lesion?) Enzyme. Phenylalanine hydroxylase Splice-site mutation: reduced amount
Tay-Sachs (Affected protein type / protein name / Molecular lesion?) Enzyme. Hexosaminidase Splice-site mutation or frameshift without stop: reduced amount
Severe combined immunodeficiency (Affected protein type / protein name / Molecular lesion?) Enzyme. Adenosine deaminase. Point mutations: abnormal protein with reduced activity
Emphysema and liver disease (Affected protein type / protein name / Molecular lesion?) Enzyme Inhibitor alpha1-antitrypsin Missense mutation: impaired secretion from liver to serum
Familial hypercholesterolemia (Affected protein type / protein name / Molecular lesion?) Receptor Low-density lipoprotein receptor Deletions, point mutations: reduction of synthesis, transport to cell surface, or binding to low density lipoprotein
Vitamin D-resistant rickets (Affected protein type / protein name / Molecular lesion?) Receptor. Vitamin D receptor Point mutations: failure of normal signaling
Alpha-Thalassemia (Affected protein type / protein name / Molecular lesion?) Oxygen transport Hemoglobin Deletions: reduced amounts
Beta-Thalassemia (Affected protein type / protein name / Molecular lesion?) Oxygen transport Hemoglobin Deletions: Defective mRNA processing: reduced amount
Sickle cell anemia (Affected protein type / protein name / Molecular lesion?) Oxygen transport Hemoglonin Point mutations: abnormal structure
Cystic fibrosis (Affected protein type / protein name / Molecular lesion?) Ion Transport Cystic fibrosis transmembrane conductance regulator Deletions and other mutations: nonfunctional or misfolded proteins
Osteogenesis imperfecta (Affected protein type / protein name / Molecular lesion?) Structural (extracellular) Collagen Deletions or point mutations cause reduced amount of normal collagen or normal amounts of defective collagen
Ehlers-Danlos (Affected protein type / protein name / Molecular lesion?) Structural (extracellular) Collagen Deletions or point mutations cause reduced amount of normal collagen or normal amounts of defective collagen
Marfan Syndrome (Affected protein type / protein name / Molecular lesion?) Structural (extracellular) Fibrillin Missense mutations
Duchenne/Becker muscular dystrophy (Affected protein type / protein name / Molecular lesion?) Structural (cell membrane) Dystrophin Deletion with reduced synthesis
Hereditary spherocytosis (Affected protein type / protein name / Molecular lesion?) Structural (cell membrane) Spectrin, ankyrin, or protein 4.1 Heterogeneous
Hemophilia A (Affected protein type / protein name / Molecular lesion?) Hemostasis Factor VIII Deletions, insertions, nonsense mutations, and others: reduced synthesis or abnormal factor VIII
Hereditary retinoblastoma (Affected protein type / protein name / Molecular lesion?) Growth regulation Rb Protein Deletions
Neurofibromatosis type 1 (Affected protein type / protein name / Molecular lesion?) Growth regulation Neurofibromin Heterogeneous
galactosemia. What is wrong? What happens? deficiency of galactose-1-phosphate uridyltransferase leads to accumulation of galactose and consequent tissue damage
what does alpha1-antitrypsin do? What happens if defective? protects tissues from neutrophil elastase. In its absence, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema and COPD
Autosomal Recessive
Congenital adrenal hyperplasia (Autosomal dominant or recessive or X-linked?) Autosomal Recessive
Alkaptonuria (Autosomal dominant or recessive or X-linked?) Autosomal Recessive
Neurogenic muscular atrophies (Autosomal dominant or recessive or X-linked?) Autosomal Recessive
Friedreich ataxia (Autosomal dominant or recessive or X-linked?) Autosomal Recessive
Spinal muscular atrophy (Autosomal dominant or recessive or X-linked?) Autosomal Recessive
All sex linked disorders are _______ and almost all are ________ all sex linked orders are X-LINKED and almost all are RECESSIVE
why is there no Y linked inheritance males with mutations affecting y-linked genes are usually infertile
Duchenne muscular dystrophy (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Hemophilia A (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Hemophilia B (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Chronic granulomatous disease (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Glucose-6-phosphate dehydrogenase deficiency (Autosomal dominant or recessive or X-linked?) and what does it do? X-linked Recessive. Predisposes red cell hemolysis in patients receiving certain types of drugs.
Agammaglobulinemia (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Wiskott-Aldrich syndrome (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Diabetes insipidus (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Lesch-Nyhan Syndrome (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Fragile-X syndrome (Autosomal dominant or recessive or X-linked?) X-linked Recessive
Tay-Sachs disease. Risk factor? Ashkenazi Jew
Phenylketonuria (Affected protein type / protein name / Molecular lesion?) Enzyme. Phenylalanine hydroxylase Splice-site mutation: reduced amount
Tay-Sachs (Affected protein type / protein name / Molecular lesion?) Enzyme. Hexosaminidase Splice-site mutation or frameshift without stop: reduced amount
Severe combined immunodeficiency (Affected protein type / protein name / Molecular lesion?) Enzyme. Adenosine deaminase. Point mutations: abnormal protein with reduced activity
Emphysema and liver disease (Affected protein type / protein name / Molecular lesion?) Enzyme Inhibitor alpha1-antitrypsin Missense mutation: impaired secretion from liver to serum
Familial hypercholesterolemia (Affected protein type / protein name / Molecular lesion?) Receptor Low-density lipoprotein receptor Deletions, point mutations: reduction of synthesis, transport to cell surface, or binding to low density lipoprotein
Vitamin D-resistant rickets (Affected protein type / protein name / Molecular lesion?) Receptor. Vitamin D receptor Point mutations: failure of normal signaling
Alpha-Thalassemia (Affected protein type / protein name / Molecular lesion?) Oxygen transport Hemoglobin Deletions: reduced amounts
Beta-Thalassemia (Affected protein type / protein name / Molecular lesion?) Oxygen transport Hemoglobin Deletions: Defective mRNA processing: reduced amount
Sickle cell anemia (Affected protein type / protein name / Molecular lesion?) Oxygen transport Hemoglonin Point mutations: abnormal structure
Cystic fibrosis (Affected protein type / protein name / Molecular lesion?) Ion Transport Cystic fibrosis transmembrane conductance regulator Deletions and other mutations: nonfunctional or misfolded proteins
Osteogenesis imperfecta (Affected protein type / protein name / Molecular lesion?) Structural (extracellular) Collagen Deletions or point mutations cause reduced amount of normal collagen or normal amounts of defective collagen
Ehlers-Danlos (Affected protein type / protein name / Molecular lesion?) Structural (extracellular) Collagen Deletions or point mutations cause reduced amount of normal collagen or normal amounts of defective collagen
Marfan Syndrome (Affected protein type / protein name / Molecular lesion?) Structural (extracellular) Fibrillin Missense mutations
Duchenne/Becker muscular dystrophy (Affected protein type / protein name / Molecular lesion?) Structural (cell membrane) Dystrophin Deletion with reduced synthesis
Hereditary spherocytosis (Affected protein type / protein name / Molecular lesion?) Structural (cell membrane) Spectrin, ankyrin, or protein 4.1 Heterogeneous
Hemophilia A (Affected protein type / protein name / Molecular lesion?) Hemostasis Factor VIII Deletions, insertions, nonsense mutations, and others: reduced synthesis or abnormal factor VIII
Hereditary retinoblastoma (Affected protein type / protein name / Molecular lesion?) Growth regulation Rb Protein Deletions
Neurofibromatosis type 1 (Affected protein type / protein name / Molecular lesion?) Growth regulation Neurofibromin Heterogeneous
galactosemia. What is wrong? What happens? deficiency of galactose-1-phosphate uridyltransferase leads to accumulation of galactose and consequent tissue damage
what does alpha1-antitrypsin do? What happens if defective? protects tissues from neutrophil elastase. In its absence, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema and COPD
what is primaquine? antimalarial drug.
if someone has an adverse reaction to primaquine, what disease do they likely have? G6PD
FBN1 Mutation leads to? (Disease and pathogenesis) Marfan syndrome results from an inherited defect in an extracellular glycoprotein called fibrillin-1. fibrillin is the major component of microfibrils in the ECM
FBN2 mutation leads to? congenital contractural arachnodactyly. An autosomal dominant disorder characterized by skeletal abnormalities
Tests have shown that anti-________ antibodies may be able to stop the vascular progression of marfan syndrome Normal microfibrils sequester TGF-beta thereby keeping it inactive. In Marfans, if you have no (or bad) microfibrils you'll get excessive TGF-beta.
dolichocephalic means "long headed". A symptom of Marfan's syndrome
what eye finding can be used to diagnose Marfans? ectopia lentis: bilateral subluxation or dislocation (usually outward and upward) of the lens
Alport Syndrome caused by mutations in collagen biosynthesis. Prevent proper production or assembly of type IV collagen, which is an important structural component of basement membranes in the kidney, inner ear, and eye.
Epidermolysis bulosa Mutation in collagen that causes the epidermis to be poorly attached to the dermis
List 4 diseases that stem from mutations affecting collagen Ehlers-Danlos Osteogenesis Imperfecta Alport syndrome Epidermolysis bullosa
what is the ultimate problem in familial hypercholesterolemia? (clinical signs?) atherosclerosis. Also causes xanthomas and arcus corneae
niemann pick disease type c NPC1 & NPC2 are needed to transport cholesterol through a hepatocyte. This disease is a disorder of NPC1/2 and causes a buildup of cholesterol
three consequences of intracellular cholesterol 1. Suppress synthesis of LDL receptors (less in) 2. activates acyl-coenzyme A which esterifies and stores cholesterol 3. suppresses cholesterol synthesis by inhibiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
how do statins work? they supress the activity of HMG CoA reductase (less cholesterol is synthesized in the hepatocyte, so more LDL receptors are made)
what is one drug class that can work in familial hypercholesterolemia? statins. Supress synthesis of cholesterol
Mannose-6-phosphate groups serve as an “address label” that is recognized by specific rectors on the inner golgi. Lysosomal enzymes bind these receptors and are thereby segregated from other secretory proteins
what does tay-sachs look like microscopically? neurons are ballooned with cytoplasmic vacoules, each representing a markedly distended lysosome filled with gangliosides
cherry red spot on the macula means you have what disease? GM2 Gangliosidosis (Tay-Sachs disease is the most common of the three)
list the 3 types of GM2 gangliosidosis Tay-Sachs disease Sandhoff disease GM2 gangliosidosis variant AB
most common lysosomal storage disease gaucher disease
tissue paper cytoplasm should make you think... gaucher disease
what is the ethnic risk factor in gaucher disease European Jews are more likely to get TYPE ONE gaucher disease
what gets built up in gaucher disease? no glucocerebrosidase, so glucocerebrosides builds up
Hurler syndrome. Another name? What protein is mutated? also called MPS 1-H. results from a deficiency of alpha-1-iduronidase.
Describe ethnic risks and course of Hurler syndrome no ethnic relation. Children appear normal at birth but develop hepatosplenomegaly by age 6 to 24 months. growth retarded and they develop coarse facial features and skeletal deformities. Death by 6 to 10 years
Hunter syndrome is also called? MPS II.
How does hunter syndrome differ from hurler syndrome? Hunter syndrome is the only MPS that is not autosomal recessive. It is x-linked recessive
how can MPS (as a class) be identified microscopically acid-Schiff-positive lysosomes
lamellated zebra bodies means: Niemann-Pick disease OR MPS
limit dextrin. What is it? What can "take care of" it? branched oligosaccharide that remains when glycogen is whittled down to about four glucose residues. Can be further degraded only by the debranching enzyme.
glycogenoses glycogen storage diseases.
List the three types of glycognoses (with principle enzyme deficiency) from table 5-7 (pg 157) von Gierke disease. Glucose-6-phosphate McArdle syndrome. Muscle phosphorylase Pompe disease. Lysosomal glucosidase (acid maltase)
what disease has hepatic and renal accumulation of glycogen? von Gierke disease (type 1)
what disease is associated with painful cramps with high serum creatine kinase mcArdle syndrome
what disease is associated with cardiomegaly and mild hepatosmegaly Pompe disease
blue black pigmentation. Another name? When do you see it? ochronosis. Alkaptonuria
what protein is messed up if you have black urine? (and what disease do you have?) Alkaptonuria. there is a lack of homogentisic oxidase.
if you have an accumulation of homogentisic acid, what disease do you have? alkaptonuria
someone has joint pain and odd looking ears. what disese? alkaptonuria
difference between hypogammaglobulinemia and agammaglobulinemia? "Hypogammaglobulinemia" is largely synonymous with "agammaglobulinemia". When this term is used (as in "X-linked agammaglobulinemia") it implies that gamma globulins are not merely reduced, but completely absent.
Created by: lbgator