Protein misfolding: alpha-1 antitrypsin deficiency: practice question

A Biochemistry question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

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Biochemistry · Protein misfolding: alpha-1 antitrypsin deficiency

Sample item

A 3-month-old girl has prolonged cholestatic jaundice. Liver biopsy shows PAS-positive, diastase-resistant globules in periportal hepatocytes. Her uncle, a non-smoker, died of panlobular emphysema. Which mechanism most directly explains the liver injury in the infant?

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

A. Retention and polymerisation of the misfolded Z variant of alpha-1 antitrypsin within the endoplasmic reticulum of hepatocytes

The Z allele (Glu342Lys) causes the protein to misfold and polymerise in the ER of hepatocytes, which is a toxic gain of function causing neonatal cholestasis and later cirrhosis. The lung disease arises from the opposite mechanism, a loss of antiprotease protection against neutrophil elastase in plasma. The retained protein shows up as PAS-positive, diastase-resistant globules.

Option by option

  • A. Retention and polymerisation of the misfolded Z variant of alpha-1 antitrypsin within the endoplasmic reticulum of hepatocytes (correct)

    Polymerised Z protein in the ER is the toxic gain-of-function that injures hepatocytes.

  • B. Failure to add mannose-6-phosphate to lysosomal enzymes

    Lack of mannose-6-phosphate tagging is the defect in I-cell disease and does not cause these globules.

  • C. Unopposed neutrophil elastase digesting hepatic parenchyma

    Unopposed elastase explains the emphysema, but it is not the cause of the hepatic lesion.

  • D. Accumulation of copper in hepatocyte lysosomes

    Copper accumulation is the mechanism of Wilson disease, which does not produce PAS-positive diastase-resistant globules.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

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Questions about this Biochemistry question

What is the answer to this Biochemistry question?

The best answer is A, Retention and polymerisation of the misfolded Z variant of alpha-1 antitrypsin within the endoplasmic reticulum of hepatocytes. The Z allele (Glu342Lys) causes the protein to misfold and polymerise in the ER of hepatocytes, which is a toxic gain of function causing neonatal cholestasis and later cirrhosis.

Why is "Failure to add mannose-6-phosphate to lysosomal enzymes" not the answer?

Lack of mannose-6-phosphate tagging is the defect in I-cell disease and does not cause these globules.

Why is "Unopposed neutrophil elastase digesting hepatic parenchyma" not the answer?

Unopposed elastase explains the emphysema, but it is not the cause of the hepatic lesion.

Why is "Accumulation of copper in hepatocyte lysosomes" not the answer?

Copper accumulation is the mechanism of Wilson disease, which does not produce PAS-positive diastase-resistant globules.

What concept does this question test?

It tests Protein misfolding: alpha-1 antitrypsin deficiency in Biochemistry. The lung disease arises from the opposite mechanism, a loss of antiprotease protection against neutrophil elastase in plasma. The retained protein shows up as PAS-positive, diastase-resistant globules.

How hard is this question?

We tag it as a multi-step question: it asks you to combine more than one idea. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study Protein misfolding: alpha-1 antitrypsin deficiency?

Build one table of enzyme deficiency, disease, inheritance and key finding, then revise it by spaced recall. Then use the flashcards and the other Biochemistry questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.