Question 1

Molecular basis of sickle cell anemia Which specific change in hemoglobin leads to sickle cell disease?

Accepted Answer

Introduction / Context: Sickle cell anemia is a classic example linking a single nucleotide polymorphism to a protein's altered physicochemical properties and a systemic phenotype. Given Data / Assumptions: The affected gene is HBB (beta-globin). The disease phenotype arises from altered hemoglobin polymerization under deoxygenation. Concept / Approach: A missense mutation substitutes valine for glutamic acid at position 6 of beta-globin (E6V). The loss of negative charge introduces a hydrophobic patch, promoting HbS polymer formation, red cell deformation, and vaso-occlusion. Step-by-Step Solution: Identify chain: beta-globin.Identify change: Glu6→Val (single point mutation).Connect to phenotype: polymerization of deoxy-HbS leads to sickling. Verification / Alternative check: Electrophoresis and DNA sequencing confirm the specific E6V substitution in HbS. Why Other Options Are Wrong: Large deletion: not the canonical cause of sickle cell disease. Delta-chain replacement: relates to HbA2, not sickle cell pathogenesis. Alpha-chain glycation: associated with diabetes biomarkers, not sickling. Extra intron insertion: not a known mechanism here. Common Pitfalls: Confusing sickle cell (E6V) with thalassemias (often deletions or splicing defects). Final Answer: A point mutation in the beta chain (Glu→Val at position 6)

Question 2

Proteins implicated in Alzheimer’s disease Which protein (historically termed A4) is directly associated with amyloid plaque formation in Alzheimer’s disease?

Accepted Answer

Introduction / Context: Alzheimer’s disease features extracellular amyloid plaques and intracellular neurofibrillary tangles. The plaque core contains amyloid-β (Aβ) peptides derived from the amyloid precursor protein historically called the A4 precursor. Given Data / Assumptions: Aβ peptides (≈40–42 aa) derive from APP via beta- and gamma-secretase cleavage. Terminology “A4” reflects older literature naming APP as A4 precursor protein. Concept / Approach: Link historical term “A4” to the modern understanding of Aβ/APP. Differentiate from proteins associated with other disorders. Step-by-Step Solution: Identify that A4 refers to APP/Aβ context.Select the option indicating amyloid-β derived from APP.Exclude proteins linked to other diseases. Verification / Alternative check: Neuropathology consistently identifies Aβ as the major plaque component, confirming the association. Why Other Options Are Wrong: Amylin: aggregates in type 2 diabetes islet amyloid, not Alzheimer’s plaques. Fibrin: coagulation protein; not the etiologic plaque protein. “Alzhemin”: not a recognized protein. Alpha-synuclein: implicated in Parkinson’s/Lewy body disease. Common Pitfalls: Confusing various amyloid-forming proteins across diseases; the context and tissue specificity are key. Final Answer: A4 (amyloid precursor protein–derived peptide, amyloid-β)

Question 3

Purine salvage defects Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) leads to which inherited disorder?

Accepted Answer

Introduction / Context: HGPRT is a key enzyme in the purine salvage pathway, recycling hypoxanthine and guanine to IMP and GMP. Its deficiency disrupts nucleotide balance and elevates uric acid production. Given Data / Assumptions: X-linked recessive inheritance pattern. Clinical triad includes hyperuricemia, neurologic dysfunction, and self-injurious behavior. Concept / Approach: Without HGPRT, purine bases are degraded rather than salvaged, increasing uric acid and reducing purine nucleotide availability in certain tissues. The classic syndrome is Lesch–Nyhan. Step-by-Step Solution: Identify pathway: purine salvage via HGPRT.Link deficiency to hallmark signs: gouty tophi, neurologic symptoms, self-mutilation.Select the named disorder: Lesch–Nyhan syndrome. Verification / Alternative check: Biochemical assays show absent or reduced HGPRT activity; genetic testing reveals HPRT1 mutations on X chromosome. Why Other Options Are Wrong: Gaucher: glucocerebrosidase deficiency (lysosomal storage), not purine salvage. Ehlers–Danlos: collagen defects. Klinefelter’s: sex chromosome aneuploidy (47,XXY). Marfan: fibrillin-1 mutation. Common Pitfalls: Confusing gout from overproduction with specific salvage enzyme deficiencies; Lesch–Nyhan is distinct due to neurological features. Final Answer: Lesch–Nyhan syndrome

Question 4

In human connective tissue disorders, defects in which structural protein are primarily responsible for the clinical features of Ehlers–Danlos syndrome (EDS)?

Accepted Answer

Introduction / Context: Ehlers–Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by hyperextensible skin, joint hypermobility, and tissue fragility. The question tests understanding of which macromolecular component underpins these clinical manifestations. Given Data / Assumptions: EDS involves weakness of connective tissues such as skin, ligaments, blood vessels, and hollow organs. Different EDS subtypes map to mutations in genes encoding structural proteins or modifying enzymes. We focus on the core structural protein affected most commonly. Concept / Approach: Connective tissue tensile strength depends largely on collagen fibrils. Many EDS types are caused by mutations in collagen genes (e.g., COL5A1/COL5A2 for classical EDS, COL3A1 for vascular EDS) or enzymes involved in collagen processing (e.g., lysyl hydroxylase). Therefore, defects in collagen biosynthesis, structure, or cross-linking explain the phenotype. Step-by-Step Solution: Identify the primary macromolecule imparting tensile strength in connective tissues: collagen.Recall that EDS commonly results from mutations in collagen type V (classical) or type III (vascular) or enzymes affecting collagen maturation.Select the option that names collagen as the defective protein class. Verification / Alternative check: Clinical genetics consistently associates EDS with collagen-related gene defects and abnormal collagen fibrillogenesis seen on ultrastructural studies, validating collagen as the key protein involved. Why Other Options Are Wrong: Elastin: important for elasticity (e.g., in Marfan-related pathways), but not the typical cause of EDS. Fibrin: involved in coagulation, not connective tissue tensile strength. Immunoglobulins (globulins): immune proteins, unrelated to EDS structural defects. Keratin: structural protein of epithelia, hair, nails; keratinopathies present differently. Common Pitfalls: Confusing EDS with Marfan syndrome (fibrillin-1 defects) or elastinopathies; assuming “any structural protein” could explain EDS when collagen defects are central. Final Answer: Collagen protein

Question 5

Antimetabolite mechanism: Methotrexate is toxic to human cells primarily because it inhibits which folate-dependent step in nucleotide biosynthesis?

Accepted Answer

Introduction / Context: Methotrexate is a classic chemotherapeutic and immunosuppressive antimetabolite. Understanding its precise biochemical target explains both its efficacy and toxicity profile in rapidly dividing cells, including bone marrow and gastrointestinal epithelium. Given Data / Assumptions: Methotrexate structurally resembles folate. Folate coenzymes (THF forms) donate one-carbon units in purine and thymidylate synthesis. Blocking THF regeneration halts DNA synthesis. Concept / Approach: Methotrexate competitively inhibits dihydrofolate reductase (DHFR), the enzyme that reduces dihydrofolate (H2 folate) to tetrahydrofolate (H4 folate). Without H4 folate, cells cannot generate 10-formyl-THF and 5,10-methylene-THF required for de novo purine and dTMP synthesis, leading to S-phase arrest and cytotoxicity in proliferating cells. Step-by-Step Solution: Identify DHFR as the key enzyme regenerating H4 folate.Connect H4 folate deficiency to impaired purine and thymidylate synthesis.Select the option explicitly stating inhibition of H2 folate reduction to H4 folate. Verification / Alternative check: Leucovorin (folinic acid), a reduced folate, rescues normal cells by bypassing DHFR blockade, confirming the site of action. Why Other Options Are Wrong: CTP formation from UTP is catalyzed by CTP synthase, not folate-dependent. PRPP synthesis is governed by PRPP synthetase; methotrexate does not inhibit this step. Thymidylate synthase uses 5,10-methylene-THF; methotrexate indirectly depletes this cofactor rather than directly inhibiting the enzyme (that is the mechanism of 5-fluorouracil). Formylation of Met-tRNAi is a prokaryotic initiation step and unrelated to methotrexate. Common Pitfalls: Confusing direct enzyme targets (TS vs DHFR); overlooking that folate antagonism affects both purine and pyrimidine pathways via THF coenzymes. Final Answer: Reduction of dihydrofolate (H2 folate) to tetrahydrofolate (H4 folate)

Question 6

Molecular pathology of sickle cell disease: During sickle cell anemia, which amino acid substitution occurs in the β-globin chain of hemoglobin?

Accepted Answer

Introduction / Context: Sickle cell disease is a classic example linking a single nucleotide change to a specific amino acid substitution and a profound clinical phenotype. Recognizing the exact substitution is foundational in genetics and molecular medicine education. Given Data / Assumptions: The mutation is in the β-globin gene (HBB). The affected residue is at position 6 of the β chain. A nonpolar residue replaces a negatively charged residue. Concept / Approach: A single A→T transversion in codon 6 alters the codon from GAG (glutamic acid) to GTG (valine). The resulting Glu6Val substitution creates a hydrophobic patch on deoxygenated hemoglobin S (HbS), promoting polymerization, red cell sickling, hemolysis, and vaso-occlusion. Step-by-Step Solution: Recall that normal β-globin has glutamic acid at position 6.In HbS, glutamic acid (acidic, charged) is replaced by valine (nonpolar).Choose the option stating Glu → Val at position 6. Verification / Alternative check: Electrophoretic mobility of HbS differs from HbA due to the charge change, supporting the identity of the substitution; DNA sequencing confirms the A→T transversion. Why Other Options Are Wrong: Valine → glutamine, Asp → Glu, or Glu → Asp do not match the known sickle mutation and would not create the same hydrophobic effect. Lys → Thr at position 6 is unrelated to HbS. Common Pitfalls: Confusing glutamine (neutral amide) with glutamic acid (acidic); mixing up the position or chain (α vs β). Final Answer: Glutamic acid → valine at position 6 (Glu6Val)

Question 7

In glycogen storage disease type I (Von Gierke disease), which enzyme is deficient and directly explains fasting hypoglycemia and lactic acidosis?

Accepted Answer

Introduction / Context: Glycogen storage diseases (GSDs) are enzyme deficiencies affecting glycogen metabolism. Von Gierke disease (GSD I) is a prototypical disorder with severe fasting hypoglycemia due to failure to release free glucose from the liver and kidney. Given Data / Assumptions: Patients present with hepatomegaly, fasting hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Defect lies in the terminal step of gluconeogenesis and glycogenolysis. Concept / Approach: Glucose-6-phosphatase hydrolyzes glucose-6-phosphate to free glucose and inorganic phosphate in the endoplasmic reticulum of hepatocytes and renal cortex. Its deficiency traps glucose-6-phosphate, preventing glucose export, driving glycolysis and lactate production, and altering lipid and uric acid metabolism. Step-by-Step Solution: Identify the shared terminal step of glycogenolysis and gluconeogenesis: conversion of G6P to glucose.Link enzyme deficiency (G6Pase) to inability to maintain blood glucose during fasting.Select “Glucose-6-phosphatase.” Verification / Alternative check: Biochemical testing shows elevated liver glycogen with normal structure; genetic testing finds G6PC or G6PT complex variants; metabolic profile matches GSD I. Why Other Options Are Wrong: Glycogen phosphorylase deficiency (Hers disease) presents differently. PFK-1 deficiency affects glycolysis (Tarui disease), not classical GSD I features. Debranching enzyme deficiency is GSD III (Cori/Forbes disease). Fructose-1,6-bisphosphatase deficiency causes gluconeogenic failure but is a distinct disorder. Common Pitfalls: Confusing GSD I with GSD III; overlooking the ER transport component (G6PT) that can phenocopy G6Pase deficiency. Final Answer: Glucose-6-phosphatase

Question 8

Osmosis and tonicity: If human red blood cells (RBCs) are placed in 0.9% NaCl (physiological saline), what change occurs to the cells?

Accepted Answer

Introduction / Context: Tonicity determines water movement across semipermeable membranes. This question reinforces the concept of isotonic solutions commonly used in clinical settings to preserve red blood cell integrity during handling and transfusion-related procedures. Given Data / Assumptions: RBC membrane is permeable to water but not to NaCl on the timescale considered. Physiological saline is 0.9% NaCl (~154 mM), isotonic with plasma. Concept / Approach: In an isotonic environment, extracellular osmolarity equals intracellular osmolarity. Therefore, there is no net water movement across the membrane, and cell volume remains stable—no hemolysis or crenation occurs. Step-by-Step Solution: Define 0.9% NaCl as isotonic relative to RBC cytosol.Predict water flux: net zero because osmotic gradients are balanced.Select the outcome: no significant change in RBC size or shape. Verification / Alternative check: In hypotonic solutions (e.g., pure water), RBCs swell and hemolyze; in hypertonic solutions (e.g., >0.9% NaCl), RBCs crenate. Neither happens in 0.9% NaCl, confirming isotonicity. Why Other Options Are Wrong: Bursting occurs in hypotonic, not isotonic, media. Shrinkage occurs in hypertonic media. Chemical destruction is not expected at physiologic NaCl concentration. Pump-mediated corrections are not needed when no gradient exists. Common Pitfalls: Confusing isotonicity (osmotic effect) with iso-osmolarity versus permeability nuances—here, NaCl behaves effectively as non-penetrating on the relevant timescale. Final Answer: No net change; cell volume remains essentially the same

Question 9

Biomolecule classification check: Which one of the following sets consists entirely of lipids (i.e., members of the same macromolecular class)?

Accepted Answer

Introduction / Context: Accurate classification of biomolecules underpins understanding of structure–function relationships in biochemistry. The question tests whether you can identify a set in which all members belong to the lipid family. Given Data / Assumptions: Lipids include diverse hydrophobic or amphipathic molecules such as triacylglycerols (fats/oils), sterols, waxes, and fatty acids. Other classes include carbohydrates, nucleic acids, and proteins. Concept / Approach: Evaluate each set for internal consistency. A correct set must contain only lipids; any presence of a carbohydrate, nucleic acid component, or protein renders the set mixed and therefore incorrect for the prompt. Step-by-Step Solution: Inspect option C: oils (triacylglycerols), sterols (cholesterol), waxes (esters of long-chain alcohols and fatty acids), fats (triacylglycerols) — all lipids.Inspect option A: ribose, sucrose, glucose, fructose — all carbohydrates, not lipids.Inspect option B: includes amino acids, which are proteins’ building blocks; the set is mixed.Inspect option D: nucleotide/nucleoside/DNA are nucleic acid-related; nucleus is an organelle, not a macromolecule class.Inspect option E: all polysaccharides (carbohydrates), not lipids. Verification / Alternative check: Textbook definitions categorize lipids by solubility in nonpolar solvents and amphipathic nature; option C meets this criterion exclusively. Why Other Options Are Wrong: A and E are carbohydrate-only sets. B includes a nonlipid (amino acids). D mixes nucleic acid components with an organelle. Common Pitfalls: Equating “oils” with non-lipid substances or assuming “nucleus” is a macromolecule; overlooking that “sterols” (e.g., cholesterol) are a lipid subclass. Final Answer: Oils, sterols, waxes, fats

Question 10

Human chromosomal aneuploidy: Klinefelter syndrome results from which sex chromosome complement?

Accepted Answer

Introduction / Context: Aneuploidies arise from meiotic nondisjunction and lead to characteristic clinical syndromes. Klinefelter syndrome is one of the most common sex chromosome aneuploidies in males, with important reproductive and endocrine consequences. Given Data / Assumptions: Phenotype: typically tall stature, small testes, gynecomastia, infertility, and variable learning differences. Karyotype involves an extra X chromosome in a phenotypic male. Concept / Approach: Klinefelter syndrome corresponds to the presence of two X chromosomes and one Y chromosome (47,XXY). Lyonization (X inactivation) occurs, but the extra X still affects gene dosage and development. Mosaic forms (e.g., 46,XY/47,XXY) also exist but the canonical form is XXY. Step-by-Step Solution: Identify the syndrome as a male with one extra X chromosome.Map this to the 47,XXY karyotype.Select XXY. Verification / Alternative check: Karyotyping and chromosomal microarray confirm the extra X; elevated FSH/LH with low testosterone supports primary testicular failure consistent with XXY. Why Other Options Are Wrong: XXX: Triple X syndrome (female), often subtle phenotype. XYY: Jacobs syndrome (male), different features. XO: Turner syndrome (female monosomy X). XXXX: rare tetrasomy with distinct female phenotype. Common Pitfalls: Confusing XXY with XYY due to both involving an extra sex chromosome; overlooking that Klinefelter refers to males with an extra X. Final Answer: XXY

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