Genetics (Part I) Flashcards by erin flaherty

There are three categories of human genetic disorders. What are they?

Mutation in a single gene with large effects (aka mendelian DOs); Chromosomal DOs; Complex multigenic DOs

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What are 6 examples of complex multigenic DOs?

Atherosclerosis, diabetes, hypertension, autoimmune diseases, height, and weight

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What do mutations in germ cells give rise to?

Inherited disease

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What do mutations in somatic cells give rise to?

Cancer and some congenital malformations

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What is a missense mutation?

When you alter the meaning of the sequence of the encoded protein

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What is a nonsense mutation?

When you insert a stop codon where it does not belong

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What is a great example of a missense mutation?

The one that occurs with sickle cell anemia: glutamic acid is changed to valine in the beta-globin chain of Hgb

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What is a great example of a nonsense mutation?

When a beta-globin chain gets changed to beta-thalassemia

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Where do the mutations of the noncoding sequences take place?

Usually in the promoter or enhancer sequence; sometimes it can be a defective splicing of intervening sequences

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What occurs in a mutation of a noncoding sequence?

There will be failure to form mRNA, so there is no translocation; or there will be changes to transcription factors such as MYC, JUN, or p53

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What happens if there is a deletion or insertion of base pairs in a multiple of 3 occurs?

The reading frame is intact and you just get an abnormal protein

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What happens if there is a deletion or insertion of base pairs not in a multiple of 3?

There is alteration in the reading frame and you get a frameshift mutation

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What is a trinucleotide repeat?

Amplification of a sequence of 3 nucleotides

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What is associated with trinucleotide repeats?

Anticipation- when a genetic disorder is passed on to the next generation, the symptoms become apparent at an earlier age with each generation

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What are 2 main examples of diseases caused by trinucleotide-repeats and have anticipation?

Huntingtons disease and myotonic dystrophy

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What is codominance?

When both alleles contribute to a phenotype

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What is pleiotropism?

When a single mutant gene has many end effects

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What is genetic heterogeneity?

Mutations at several loci may produce the same trait

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There are three transmission patterns of single gene disorders. What are they?

Autosomal dominant, autosomal recessive, and X-linked

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What are 2 examples of autosomal dominant disorders that affect the nervous system?

Huntington disease and neurofibromatosis

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What are 3 examples of autosomal dominant disorders that affect the skeletal system?

Marfan syndrome, Ehlers-Danlos syndrome, and osteogenesis imperfecta

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What is 1 example of an autosomal dominant disorder that affect the metabolic system?

Familial hypercholesterolemia

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Autosomal dominant disorders are manifested in what state?

Heterozygous- so at least one parent is usually affected

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When do new autosomal dominant mutations tend to occur?

In germ cells of relatively older fathers

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There are variations in penetrance and expressivity in autosomal dominant disorders. What is incomplete penetrance?

When there is a mutation but a normal phenotype

There are variations in penetrance and expressivity in autosomal dominant disorders. What is variable expressivity?

Everybody has a trait, but it is expressed differently

What is the best example of variable expressivity?

Neurofibromatosis type 1: patients could have café-au-lait spots or not, skeletal deformities or not, and/or neurofibromas

Sometimes with autosomal dominant disorders you can get decreased product, dysfunctional, or inactive product produced. What is an example of a loss-of-function autosomal dominant mutation?

Familial hypercholesterolemia

Sometimes with autosomal dominant disorders you can get decreased product, dysfunctional, or inactive product produced. What is an example of a gain-of-function autosomal dominant mutation?

Huntington protein toxic to neurons

There are 2 main patterns of disease that we can see with autosomal dominant mutations. What are they?

Regulation of complex metabolic pathways subject to feedback inhibition; key structural proteins problems

What is an example of the autosomal dominant disease pattern that affects the regulation of complex metabolic pathways?

The LDL receptor in familial hypercholesterolemia

What is an example of the autosomal dominant disease pattern that affects the key structural protein (such as collagen and cytoskeletal elements of the RBC membrane)?

Osteogenesis imperfecta

What is the typical age of onset in many autosomal dominant disorders?

Age of onset is delayed in many autosomal dominant conditions; symptoms appear in adulthood

What are 2 examples of autosomal recessive disorders that affect the metabolic system?

Cystic fibrosis and phenylketonuria

Almost ALL inborn errors of metabolism are what?

Autosomal recessive

What is the largest category of disorders?

Autosomal recessive

What are 3 features of autosomal recessive disorders?

The trait usually does not affect the parent; siblings have a 1 in 4 chance of having the trait (25% risk each birth), if the mutation is of low frequency in population, there is a strong likelihood proband product of consanguineous marriage

How does an autosomal recessive disorder manifest on the alleles?

Both alleles are affected

How can you differentiate between autosomal recessive and autosomal dominant?

In autosomal recessive, the expression of the defect is more uniform than AD(everybody with the disease has a similar presentation); complete penetrance is common in AR; the onset of AR is early in life; many mutations involve enzymes in AR; new mutations in AR diseases can take generations to become evident

The primary defect in cystic fibrosis results from abnormal function of an epithelial chloride channel protein encoded by the cystic fibrosis transmembrane conductance regulator gene on what chromosome?

7q31.2

Cystic fibrosis is the most common lethal genetic disease that affects what population?

Caucasian populations

What is the effect of heterozygote carriers of cystic fibrosis?

Although cystic fibrosis follows an autosomal recessive transmission pattern, recent data suggests that even heterozygote carriers have a higher incidence of respiratory and pancreatic diseases as compared with the general population

What is the most common organism to colonize cystic fibrosis patients?

Pseudomonas aeruginosa

What are the gastrointestinal and nutritional abnormalities seen with cystic fibrosis patients?

Meconium ileus and pancreatic insufficiency

What population is PKU common in?

Caucasians primarily of Scandinavian descent

What causes PKU?

An autosomal recessive mutation that causes a deficiency in phenylalanine hydroxylase (PAH); so phenylalanine cannot be converted into tyrosine

How does onset of PKU present?

The patient is normal at birth, but as the phenylalanine accumulates, there is intellectual disability, hypopigmentation of the hair and skin, and eczema; there will also be a strong musty or mousy odor in urine and sweat

What is an example of an X-linked recessive disorder that affects the blood?

Glucose-6-phosphate dehydrogenase deficiency (G6PD)

What is an example of an X-linked recessive disorder that affects the nervous system?

Fragile X syndrome

What is the inheritance pattern of X-linked recessive disorders?

Males are usually infertile, hence there is no Y-linked inheritance; all daughters of affected male are carriers

What is the inheritance pattern of mitochondrial inheritance?

A female will pass the trait to all of her children; the male does not pass the trait on to any of their children

What is an example of a mendelian disorder that affects an enzyme?

Tay-Sachs disease

What is an example of a mendelian disorder that affects a receptor?

Familial hypercholesterolemia

What is an example of a mendelian disorder that affects an ion channel?

Cystic fibrosis

What are the characteristics of a Mendelian disorder?

There is an alteration in a single gene leading to an abnormal product or a decrease in normal product

There are four main categories of mendelian disorders. What are they?

Enzyme defects, defects in receptors and transport systems, alterations in structure function or quantity of non-enzyme proteins, and mutations resulting to unusual reactions to drugs

What are the 3 major consequences of mendelian disorders that cause enzyme defects?

Accumulation of the substrate, decreased amount of end product, or failure to inactivate a tissue-damaging substrate

What is an example of a mendelian disorder that causes an enzyme defect that leads to an accumulation of substrate?

Galactosemia

What is an example of a mendelian disorder that causes an enzyme defect that leads to a decreased amount of end product? (2 examples)

Albinism and Lesch-Nyhan

What is an example of a mendelian disorder that causes an enzyme defect that leads to failure to inactivate a tissue-damaging substrate?

Alpha1-antitrypsin deficiency inability to inactivate neutrophil elastase in the lung leading to emphysema

What should patients with alpha1-antitrypsin avoid?

Cigarette smoking because smoking markedly accelerate emphysema

What mutation is associated with an alpha1-antitrypsin deficiency?

PiZ- homozygotes for the PiZZ protein have circulating alpha1-antitrypsin levels that are only 10% of normal

What are PiZZ adults at risk for?

Hepatocellular carcinoma

2 examples of mendelian disorders that cause alterations in structure, functions, or quantity of non-enzyme proteins?

Sickle cell disease and Thalassemias

What is an example of a mendelian disorder that causes adverse reactions to drugs?

G6PD deficiency and the antimalarial drug primaquine this combination will cause severe hemolytic anemia

What are 2 examples of disorders associated with defects in structural proteins?

Marfan syndrome and Ehlers-Danlos Syndrome

Marfan’s syndrome is an autosomal dominant syndrome that affects what gene on what chromosome?

FBN1 on chromosome 15q21.1 or FBN2 on chromosome 5q23.31 (less common)

What happens when there is a mutation in the FBN1/2 gene?

There is a defect in an extracellular glycoprotein called fibrillin-1

How does loss of fibrillin lead to the clinical manifestations?

Either by a loss of structural support in microfibril-rich connective tissue or through excessive activation of TGF-beta signaling

Where are microfibrils found?

They are abundant in the aorta, ligaments, and ciliary zonules that support the lens

What is the specific effect of a fibrillin-2 (FBN2) mutation?

Congenital contractural arachnodactyly

What happens if there is excessive activation of TGF-beta signaling?

Bone overgrowth and myxoid changes in mitral valves; leads to inflammation, has deleterious effects on vascular smooth muscle development, and increased activity of metalloproteases which leads to a loss of extracellular matrix