Haemoglobinopathies: HbE as a splicing variant: 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 · Haemoglobinopathies: HbE as a splicing variant

Sample item

A 7-year-old boy from Assam has moderate microcytic anaemia. Electrophoresis shows HbE and HbF with no HbA; his father has HbE trait and his mother has beta-thalassaemia trait. HbE (Glu26Lys) behaves like a mild beta-thalassaemia allele. What is the molecular basis?

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

The answer and the reasoning

C. The G-to-A change at codon 26 activates a cryptic splice site in exon 1, reducing normal mRNA

The HbE mutation (GAG to AAG at codon 26) not only substitutes lysine for glutamate but also creates a sequence that activates a cryptic donor splice site in exon 1. A proportion of transcripts are mis-spliced, so the amount of beta-E globin is reduced and the allele behaves as a mild beta-plus thalassaemia. Compound heterozygosity with a beta-zero allele (HbE-beta thalassaemia) causes variable severity and is common in eastern and north-eastern India.

Option by option

  • A. A nonsense mutation at codon 26 triggers nonsense-mediated decay of all transcripts

    HbE is a missense change and not a nonsense mutation, so nonsense-mediated decay is not responsible.

  • B. A promoter deletion abolishes transcription of the beta-globin gene on that chromosome

    The beta-globin promoter is intact in HbE, and promoter defects cause other mild beta-thalassaemia alleles.

  • C. The G-to-A change at codon 26 activates a cryptic splice site in exon 1, reducing normal mRNA (correct)

    Cryptic splice site activation explains reduced output of HbE and the thalassaemia-like phenotype.

  • D. Deletion of the whole beta-globin gene cluster on the affected chromosome

    Gene cluster deletion would cause absent beta chains and is not the nature of HbE.

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 C, The G-to-A change at codon 26 activates a cryptic splice site in exon 1, reducing normal mRNA. The HbE mutation (GAG to AAG at codon 26) not only substitutes lysine for glutamate but also creates a sequence that activates a cryptic donor splice site in exon 1.

Why is "A nonsense mutation at codon 26 triggers nonsense-mediated decay of a…" not the answer?

HbE is a missense change and not a nonsense mutation, so nonsense-mediated decay is not responsible.

Why is "A promoter deletion abolishes transcription of the beta-globin gene o…" not the answer?

The beta-globin promoter is intact in HbE, and promoter defects cause other mild beta-thalassaemia alleles.

Why is "Deletion of the whole beta-globin gene cluster on the affected chromo…" not the answer?

Gene cluster deletion would cause absent beta chains and is not the nature of HbE.

What concept does this question test?

It tests Haemoglobinopathies: HbE as a splicing variant in Biochemistry. A proportion of transcripts are mis-spliced, so the amount of beta-E globin is reduced and the allele behaves as a mild beta-plus thalassaemia. Compound heterozygosity with a beta-zero allele (HbE-beta thalassaemia) causes variable severity and is common in eastern and north-eastern India.

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 Haemoglobinopathies: HbE as a splicing variant?

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.