Genetics/Biochemistry

Question 1

What is pleiotropy?

Answer 1

The occurrence of multiple, seemingly unrelated phenotypic manifestations (e.g. homocystinuria - skeletal abnormalities, lens dislocation, intellectual disabilities, vascular thromboses)

Question 2

Supplementation with which vitamin may help improve the symptoms of maple syrup urine disease?

Answer 2

Thiamin (B1) - cofactor for branched-chain alpha-ketoacid dehydrogenase. This part of several enzymes referred to as the branched-chain alpha-ketoacid dehydrogenase complex (BCKDC). This is required for degredation of branched-chain amino acids (leucine, isoleucine, and valine). Branched-chain alpha-ketoacid dehydrogenase requires 5 cofactors: Thiamine, Lipoate, Coenzyme A, FAD, NAD (“Tender Loving Care For Nancy”).

Question 3

What are the stop codons?

Answer 3

UAA, UAG, & UGA

Question 4

What enzyme is deficient in Ehler’s-Danlos syndrome?

Answer 4

Can be caused by a deficient in procollagen peptidase, which is the enzyme responsible for cleaving terminal propeptides from procollagen in the extracellular space (N- & C- terminal peptides are cleaved)

Question 5

What are the DNA signals for splicesomes to remove introns.

Answer 5

GU at the 5’ splice site and AG at the 3’ splice site

Question 6

Where are enhancer sequences located?

Answer 6

They can be upstream or downstream of the gene, or even within introns or on separate chromosomes from the target gene.

Question 7

What are the nonpolar, hydrophobic amino acids?

Answer 7

Alanine, valine, leucine, isoleucine, phenylalanine, proline and glycine. These are frequently components of the transmembrane domain of proteins.

Question 8

Which RNA polymerase functions exclusively in the nucleolus?

Answer 8

RNA polymerase I. It exclusively transcribes the 45S pre-rRNA gene into a single template that is subsequently processed into mature 18S, 5.8S and 28S rRNAs.
The nucleolus of malignant cells is often prominent due to the large number of active rRNA genes.

Question 9

What is MERRF?

Answer 9

Myoclonic epilepsy with ragged red fibers. Mitochondrial inheritance.

Question 10

What diseases are inherited via mitochondrial inheritance?

Answer 10

Myoclonic epilepsy with ragged red fibers (MERRF), Leber optic neuropathy (blindness), and mitochondrial encephalopathy with stroke-like episodes and lactic acidosis (MELAS)

Question 11

What is Jervell and Lange-Nielsen syndrome?

Answer 11

An autosomal recessive disorder characterized by profound bilateral sensorineural hearing loss and congenital long QT syndrome. It is due mutations in genes that encode alpha and beta subunits of voltage-gated potassium channels (e.g. KCNA1, KCNE1).

Question 12

How is diagnosis of methylmalonyl-CoA mutase deficiency made?

Answer 12

Elevated urine methylmalonic acid and propionic acid are diagnostic. This causes a metabolic acidosis which leads to an increased metabolic rate causing hypoglycemia, increased ketones (increased fat metabolism, increases the anion gap), and hyperammonemia. Presents in the neonatal period with poor feeding and lethargy.

The enzyme is involved in branched-chain amino acid metabolism. Uses B12 as a cofactor.

Question 13

What are features of arginase deficiency?

Answer 13

Progressive development in childhood of spastic diplegia (stiffness of the lower extremities), abnormal movements, and growth delay in the setting of elevated arginine levles. Arginase is part of the urea cycle and produces urea and ornithine from arginine.

Question 14

What hereditary enzyme deficiency in heterozygotes predisposes patients to maturity-onset diabetes of the young?

Answer 14

Glucokinase. This can be worsened by pregnancy-induced insulin resistance.

Question 15

What blood disorder do glycolytic enzyme deficiencies (e.g. aldolase A, enolase, phosphofructokinase, pyruvate kinase) cause?

Answer 15

Hemolytic anemia, as RBCs rely completely on anaerobic glycolysis for energy production.

Question 16

What does calcium bind to in skeletal muscle?

Answer 16

Troponin

Question 17

What diseases does multiple endocrine neoplasia type 1 (MEN 1) predispose patients to?

Answer 17

Primary hyperparathyroidism (hypercalcemia), pituitary tumors (prolactin, visual defects), and pancreatic tumors (especially gastrinomas - Zollinger-Ellison syndrome).

Question 18

What diseases does multiple endocrine neoplasia type 2A (MEN 2A) predispose patients to?

Answer 18

Medullary thyroid cancer (calcitonin), pheochromocytoma, parathyroid hyperplasia.

Question 19

What diseases does multiple endocrine neoplasia type 2B (MEN 2B) predispose patients to?

Answer 19

Medullary thyroid cancer (calcitonin), pheochromocytoma, mucosal neuromas/marfanoid habitus.

Question 20

What are some common conditions that demonstrate polygenic inheritance patterns?

Answer 20

Androgenetic alopecia, epilepsy, glaucoma, hypertension, ischemic heart disease, schizophrenia, Type II DM.

Question 21

What molecules is riboflavin (vitamin B2) a precursor for?

Answer 21

Riboflavin is first phosphorylated to become flavin mononucleotide (FMN), which can be further phosphorylated to flavin adenine dinucleotide (FAD). FAD acts as a cofactor with succinate dehydrogenase (gets reduced so it can participate in the electron transport chain as FADH2). Deficiency leads to glossitis, cheilitis, angular stomatitis, seborrheic dermatitis, eye changes (e.g. keratitis, corneal neovascularization), and anemia.

Question 22

What is the most common cystic fibrosis defect?

Answer 22

ΔF508 mutation. This causes a 3-base pair deletion which impairs post-translational processing leading to misfolding and improper glycosylation of the CFTR protein. As a result, the abnormal protein is targeted for proteasomal degradation, preventing it from reaching the cell surface.

Question 23

What is the manifestation of ornithine transcarbamylase (OTC) deficiency?

Answer 23

It is the most common urea cycle disorder. It results in excess carbamoyl phosphate, which stimulates pyrimidine synthesis. An intermediate product in this pyrimidine synthesis pathway is orotic acid which accumulates and results in increased urinary orotic acid. These patients also have hyperammonemia due to impaired ammonia excretion (OTC is part of the urea cycle). Ammonia is neurotoxic and can cause episodes of vomiting and confusion/coma. Tachypnea also occurs due to cerebral edema from ammonia buildup, resulting in central hyperventilation and respiratory alkalosis. Metabolic decompensation is often triggered by illness, fasting, or increased protein intake.

Question 24

What process is the enzyme glycerol kinase involved in?

Answer 24

The breakdown of glycerol to dihydroxyacetone phosphate (DHAP), which can then be used for gluconeogenesis or glycolysis.

Triglycerides stored in adipose tissue are metabolized to free fatty acids and glycerol by hormone-sensitive lipase in response to low insulin and high catecholamine levels. Adipocytes are unable to metabolize glycerol, so it is secreted into the circulation and transported to the liver, where it is phosphorylated to glycerol-3-phosphate by glycerol kinase. Glycerol-3-phosphate is subsequently converted by glycerol-3-phosphate dehydrogenase to DHAP.

Question 25

What is the Kozak consensus sequence?

Answer 25

Found in eukaryotes used to initiate translation of mRNA (analogous to the Shine-Dalgarno sequence in E. coli). It is defined by the following sequence: (gcc)gccRccAUGG, where R is either adenine (A) or guanine (G). Among other factors, a purine (A or G) positioned 3 bases upstream from AUG appears to play a key role in this initiation process.

Question 26

What is the Shine-Dalgarno sequence?

Answer 26

Found in prokaryotes. Used to initiate translation of mRNA. The sequence is AGGAGGU.

Question 27

What is Friedreich ataxia?

Answer 27

An AR disorder caused by a mutation of the frataxin (FXN) gene (increased GAA trinucleotide repeats), which codes for an essential mitochondrial protein involved in the assembly of iron-sulfur enzymes. This causes decreased mitochondrial energy production and increased oxidative stress, resulting in degeneration of neural tracts (dorsal column and dorsal root ganglia [loss of position and vibration sense], lateral corticospinal [spastic muscle weakness], and spinocerebellar [ataxia] tracts) and peripheral nerves. Patients also get kyphoscoliosis and foot abnormalities (pes cavus), as well as hypertrophic cardiomyopathy and CHF. Diabetes mellitus develops in ~10% of patients.

Question 28

What enzyme is deficient in xeroderma pigmentosum?

Answer 28

It is characterized by defects in nucleotide excision repair (deficiency in UV-specific endonuclease).

Question 29

What is the sequence of base excision repair?

Answer 29

Glycosylase cleaves the altered base leaving an empty sugar-phosphate site (apurinic/apyrimidinic [AP] site) → endonucleases cleaves the 5' end → lyase cleaves the 3' sugar-phosphate → DNA polymerase fills in the gap → ligase seals the nick

Question 30

What inheritance pattern does spina bifida demonstrate?

Answer 30

Multifactorial - neural tube defects are more common in first-degree relatives of those affected, with a recurrence risk of 2%-5%. Other multifactorial diseases include cleft lip and palate, diabetes mellitus, coronary artery disease, and hypertension.

Question 31

Why is huntington gene expression decreased in Huntington Disease?

Answer 31

The CAG trinucleotide repeat leads to increased histone deacetylation, thus causing transcriptional repression (silencing)

Question 32

What is porphyria cutanea tarda (PCT)?

Answer 32

A defect in a late step in porphyrin (e.g. heme) synthesis. Most commonly due to a deficiency of uroporghyrinogen decarboxylase (UROD), but can also be caused by deficiencies in coproporphyrinogen oxidase, protoporphyrinogen oxidase, or ferrochelatase. More commonly it is acquired than inherited (acquired in setting of alcohol, smoking, halogenated hydrocarbons, hepatitis C, and HIV). It causes photosensitivity (blisters and vesicles in sites of sun exposure). Note that early steps in porphyrin synthesis cause abdominal pain and neuropsychiatric manifestations rather than photosensitivity (e.g. ALA dehydratase).

Question 33

What is Hartnup disease?

Answer 33

AR disorder caused by inactivating mutations affecting the neutral amino acid transporter. This results in impaired transport of neutral amino acids, particularly tryptophan, in the small intestine and the proximal convoluted tubule. Tryptophan is the precursor for niacin, serotonin, and melatonin. Patients can get pellagra-like skin eruptions and cerebellar ataxia. Diagnosis is made by the presence of neutral amino acids (alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, and tryptophan) in the urine. Treated with a high-protein diet and daily niacin supplementation.

Question 34

What 2 electrolytes are decreased in patients with cystic fibrosis?

Answer 34

Sodium and chloride. Patients are unable to reabsorbe chloride and sodium in the eccrine ducts (why sweat chloride tests are done to diagnose CF). Exclusively breast fed infants are at risk for hyponatremia if they do not receive sodium supplementation.

Question 35

What cofactor is necessary for transamination reactions (e.g. transferring an amino group between an alpha-keto acid and an amino acid)?

Answer 35

Pyridoxine (vitamin B6). It is also required for the decarboxylation of amino acids. In transamination reactions, it serves as a cofactor for aminotransferases (e.g. AST and ALT)

Question 36

What is the appearance of osteoclasts in Paget's disease of bone?

Answer 36

Osteoclasts are typically very large and can have up to 100 nuclei (normal osteoclasts have 2-5 nuclei).

Question 37

What is alkaptonuria?

Answer 37

An AR disorder caused by a deficiency of homogentisic acid dioxygenase (metabolizes homogentisic acid into maleylacetoacetate - part of the break down of phenylalanine and tyrosine to be used in the TCA cycle). Accumulation of homogentisic acid causes pigment depositis in connective tissue throughout the body. During adulthood, these blue-black deposits become apparent in the sclerae and ear cartilage. Deposits also occur in large joints and the spine, causing ankylosis, motion restriction, and significant pain. They may have black urine when exposed to the air due to the oxygenation of homogentisic acid.

Question 38

What is heteroplasmy?

Answer 38

Heteroplasmy is the presence of more than one type of organellar genome (e.g. mitochondria) within a cell or an individual. It is important for determining the severity of mitochondrial illnesses.

Question 39

NADPH is necessary for generation of what compounds?

Answer 39

Necessary for the biosynthesis of cholesterol, fatty acids, and steroids. It is also necessary for reducing glutathione and is used by phagocytic cells generating a respiratory burst via NADPH oxidase.

Question 40

What is I-cell disease?

Answer 40

AR lysosomal storage disorder (defects in protein targeting - defect in a Golgi body phosphotransferase enxyme that catalyzes the phosphorylation of mannose residues in order to target proteins to the lysosome). Presents in infancy with failure to thrive, cognitive deficits, coarse facial features, and corneal clouding. Often fatal in childhood.

Question 41

What enzymes does fructose-2,6-bisphosphate regulate?

Answer 41

Activates phosphofructokinase-1 (promotes glycolysis) and inhibits fructose-1,6,-bisphosphatase (inhibits gluconeogenesis)

Question 42

What is a test that can detect the presence of fructose, galactose, or glucose in the urine (non-specific test as it does not distinguish between sugar types)?

Answer 42

A copper reduction test. Fructose, galactose and glucose are all reducing sugars. Note that a urine dipstick uses glucose oxidase to ascertain the presence of urinary glucose and will not test positive in the presence of fructose or galactose.

Question 43

What genes are most commonly mutated in Lynch syndrome (autosomal dominant defect in DNA mismatch repair)?

Answer 43

MSH2, MLH1, MSH6, and PMS2

Question 44

What cancers are patients at risk for in Lynch syndrome?

Answer 44

Colorectal, endometrial, and ovarian

Question 45

What is Southwestern blotting?

Answer 45

Uses a labeled DNA probe to detect DNA-binding proteins such as transcription factors (e.g. c-Jun, c-Fos), nucleases, and histones.

Question 46

What is the inheritance pattern of G6PD deficiency?

Answer 46

X-linked recessive

Question 47

What are the two forms of galactosemia?

Answer 47

1. Galactokinase (GALK) deficiency: milder, cataracts may be the only manifestation due to a build up of galactitol in the eye (GALK catalyzes the conversion of galactose to galactose-1-phosphate. Galactose builds up and is shunted down an alternate pathway and converted to galactitol). Excess galactose spills into urine causing a positive reducing substance test. 2. Galactose-1-phosphate uridyl transferase (GALT) deficiency: presents in the neonatal period with vomiting, lethargy, and failure to thrive. GALT catalyzes the conversion of galactose-1-phosphate to glucose-1-phosphate which may then be converted to glucose-6-phosphate. In GALT deficiency, galactose-1-phosphate builds up, which is a toxic metabolite that causes hepatic and renal dysfunction.

Question 48

What step in the TCA cycle produces GTP?

Answer 48

Succinyl-CoA to succinate

Question 49

What infection are infants with galactose-1-phosphate uridyl transferase (GALT) deficiency at risk for?

Answer 49

E. coli sepsis. GALT catalyzes the conversion of galactose-1-phosphate to glucose-1-phosphate (using UDP-glucose [converted to UDP-galactose])

Question 50

What is Rett syndrome?

Answer 50

Neurodevelopmental disorder that primarily affects girls (X-linked mutation of the MECP2 gene). Characterized by normal development until age 5-18 months, followed by loss of motor and language skills and the development of stereotypic hand movements. Deceleration of head growth is a classic feature.

Question 51

What are 5 features of anaplastic tumors?

Answer 51

1. Loss of cell polarity with complete disruption of normal tissue architecture. 2. Cellular pleomorphism and nuclear pleomorphism. 3. High N:C ratio. 4. Numerous mitotic figures. 5. Giant, multinucleated tumor cells.

Question 52

What kind of gate is the CFTR (cystic fibrosis transmembrane conductance regulator) channel?

Answer 52

ATP-gated

Question 53

What fatty acids must undergo a special form of oxidation in the peroxisome (i.e. cannot undergo mitochondrial beta-oxidation)?

Answer 53

Very long chain fatty acids (VLCFA) via beta oxidation and branched chain fatty acids (e.g. phytanic acid) via alpha oxidation.

Question 54

What is Zellweger syndrome?

Answer 54

Deficiency of peroxisomes. In this condition, infants are unable to properly form myelin in the CNS. Symptoms include hypotonia, seizures, hepatomegaly, mental retardation, and early death within months of initial presentation. It is due to a build up of fatty acids that must be broken down in the peroxisomes (e.g. very long chain fatty acids and phytanic acid).

Question 55

What is Refsum disease?

Answer 55

Defect of peroxisomal alpha oxidation that leads to neurologic disturbances due to the accumulation of phytanic acid in the body. Treatment is strict avoidance of chlorophyll in the diet.

Question 56

What is ataxia-telangiectasia?

Answer 56

An AR disorder resulting from a defect in DNA-repair genes (problem with nonhomologous end joining). The DNA of these patients is hypersensitive to ionizing radiation. Manifestations include cerebellar ataxia, oculocutaneous telangiectasias, repeated sinopulmonary infections, and an increased incidence of malignancy.

Question 57

What are neurophysins?

Answer 57

Carrier proteins for oxytocin and vasopressin. Mutations to neurophysin II (autosomal dominant) which preferentially binds to vesopressin can cause hereditary hypothalamic diabetes insipidus.

Question 58

What is the only bacterial DNA polymerase with 5' to 3' exonuclease activity?

Answer 58

DNA polymerase I (DNA polymerase III has 5' to 3' polymerase and 3' to 5' exonuclease activity). This action removes RNA primers in the lagging strand.

Question 59

What hepatic enzyme metabolizes pro-carcinogens?

Answer 59

Cytochrome P450 monooxygenase metabolizes steroids, alcohols, toxins, and other foreign substances by rendering them soluble and easier to excrete. Unfortunately, this metabolic processing also converts pro-carcinogens into carcinogens capable of causing mutations in human DNA.

Question 60

Retinoblastoma (Rb) gene mutations put patients at risk for what cancers?

Answer 60

Retinoblastoma and osteosarcoma

Question 61

What does the HAMARTOMAS mnemonic in tuberous sclerosis refer to?

Answer 61

``` H: Hamartomas in CNS and skin A: Angiofibromas (facial) M: Mitral regurgitation A: Ash-leaf spots R: cardiac Rhabdomyoma T: (Tuberous sclerosis) O: autsomal dOminant M: Mental retardation A: renal Angiomyolipoma S: Seizures and Shagreen patches ```

Question 62

Eating excessive egg whites can cause what vitamin deficiency? What does this vitamin deficiency look like?

Answer 62

Biotin (due to high levels of biotin-binding avidin in egg whites). Changes in mental status, myalgias, anorexia, and chronic dermatologic changes such as macular dermatitis. Patients can develop metabolic acidosis as a result of increased conversion of pyruvate to lactic acid.

Question 63

What enzymes are biotin a cofactor for?

Answer 63

Carboxylases (e.g. pyruvate carboxylase which converts pyruvate to oxaloacetate to be used for gluconeogenesis).

Question 64

How do amatoxins found in poisonous mushrooms exert their toxic effects (i.e. what is their target)?

Answer 64

Inhibit DNA-dependent RNA polymerase II, thus preventing the transcription of mRNA. Diagnosed by the presence of alpha-amanitin in urine.

Question 65

What is the sequence at the 3' hydroxyl (amino acid binding site) end of tRNA?

Answer 65

CCA

Question 66

What 3 molecules can be used to make NAD+?

Answer 66

Niacin, tryptophan, and nicotinamide

Question 67

What are features of myotonic muscular dystrophy?

Answer 67

Difficulty loosening one's grip, cataracts, frontal balding and gonadal atrophy. AD, trinucleotide repeat expansion of CTG, demonstrates anticipation.

Question 68

What type of reactions is B6 (pyridoxine) involved in?

Answer 68

Transamination (e.g. AST, ALT) and decarboxylation

Question 69

What type of reactions is B1 (thiamin) involved in?

Answer 69

Dehydrogenase reactions (e.g. transketolase, alpha-ketoglutarate dehydrogenase, and pyruvate dehydrogenase)

Question 70

What type of reactions is biotin (B7) involved in?

Answer 70

Cofactor for 4 carboxylase enzymes: pyruvate carboxylase, acetyl-CoA carboxylase, propinoyl-CoA carboxylase, and 3-methylcrotonyl-CoA-carboxylase

Question 71

What problems does a dopamine beta-hydroxylase deficiency cause?

Answer 71

It converts dopamine to norepinephrine so there is impaired sympathetic adrenergic activity. This leads to hypotenson, ptosis (infants), hypothermia (infants), exercise intolerance, nasal congestion, and ejaculatory difficulties.

Question 72

What vimentin a marker of (intermediate filament)?

Answer 72

Mesenchymal tissue (e.g. fibroblasts, endothelial cells, macrophages). Used to mark sarcomas

Question 73

What is Leber hereditary optic neuropathy?

Answer 73

Mitochondrial inherited disorder characterized by bilateral optic neuropathy leading to blindness

Question 74

What is Rett syndrome?

Answer 74

X-linked dominant disorder affecting females (males die in utero) that presents with progressive neurodegeneration and stereotypical hand movements.

Question 75

Where does hydroxylation of proline and lysine residues in collagen take place in the cell?

Answer 75

The rough endoplasmic reticulum

Question 76

How does activation of the phosphatidylinositol-3-kinase (PI3K) pathway by binding of insulin to the insulin receptor cause glycogen synthesis?

Answer 76

By activating protein phosphatase which dephosphorylates glycogen synthase, leading to its activation.

Question 77

What causes the decreased expression of the huntingtin gene in Huntington Disease?

Answer 77

Histone deacetylation

Question 78

During apoptosis, activation of the caspases results in eIF degradation (to decrease protein synthesis). How do cells continue to translate proteins needed for apoptosis when eIF is decreased?

Answer 78

Through an alternative method called internal ribosomal entry. A distinct nucleotide sequence called the internal ribosome entry site (IRES) attracts the eukaryotic ribosome to mRNA and allows for translation to begin. IRESs are usually located in the 5' untranslated region, upstream of the start codon.

Question 79

What is hand-foot-genital syndrome?

Answer 79

A defect of the HOXA13 homeobox gene. AD. Characterized by malformations of the distal limbs (e.g. hypoplastic first digits) and Müllerian fusion abnormalities (e.g. uterus didelphys - can cause miscarriages).

Question 80

What are the ketogenic amino acids? | What are the amino acids that are both ketogenic and glucogenic?

Answer 80

Ketogenic="L's": Leucine and lysine | Ketogenic and glucogenic = "PITTT": phenylalanine, isoleucine, tryptophan, tyrosine, threonine