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Difficulty: MediumGenetic and Molecular Mechanisms

A 29-year-old pregnant woman comes to the outpatient clinic due to a 2-year history of progressive weakness in her hands. She notes that she often has difficulty releasing her grip after turning a doorknob or shaking hands. The patient also reports excessive daytime sleepiness. Her family history is significant for her mother, who developed cataracts in her 40s and currently has severe distal muscle weakness. Physical examination reveals wasting of the temporalis and masseter muscles, as well as a prominent delay in hand opening after forcefully gripping the examiner's fingers. Electrocardiogram shows a first-degree atrioventricular block. Based on the patient's presentation and family history, which of the following best describes the molecular mechanism underlying her most likely diagnosis?

  1. Expanded nucleotide repeats in a non-coding region leading to abnormal mRNA processingAnswer
  2. B
    Expanded nucleotide repeats in a coding region resulting in toxic protein aggregation
  3. C
    Promoter hypermethylation leading to transcriptional silencing of the affected gene
  4. D
    Out-of-frame deletion resulting in a truncated, non-functional cytoskeletal protein
  5. E
    Missense mutation resulting in a defective structural glycoprotein with dominant negative effects

Answer

Expanded nucleotide repeats in a non-coding region leading to abnormal mRNA processing
The correct answer accurately describes the pathophysiology of Myotonic Dystrophy Type 1 (DM1). DM1 is an autosomal dominant disorder typically caused by an abnormal expansion of CTG trinucleotide repeats in the 3' untranslated region of the DMPK gene. Because these repeats are in a non-coding region, they do not alter the amino acid sequence of a protein. Instead, the abnormally long mRNA transcripts remain trapped in the nucleus and bind strongly to critical RNA-splicing factors (such as MBNL1). This sequestration leads to widespread errors in the alternative splicing of numerous other cellular mRNAs, a phenomenon known as RNA toxicity or a spliceopathy. For example, abnormal splicing of the muscle chloride channel mRNA leads to the characteristic myotonia, while abnormal splicing of the insulin receptor mRNA causes insulin resistance. This patient's presentation of myotonia, facial muscle wasting, early-onset cataracts, and an AV block is classic for DM1.

Step-by-Step Solution

1
Analyze the clinical presentation and family history to establish the most likely diagnosis.
The combination of myotonia (delayed grip release), distal muscle weakness, temporalis wasting, cataracts, and cardiac arrhythmias (first-degree AV block) in the context of an autosomal dominant inheritance pattern is classic for Myotonic Dystrophy Type 1 (DM1).
Identifying the specific clinical syndrome is the necessary first step before evaluating the underlying molecular pathophysiology.
2
Determine the genetic mutation and molecular mechanism responsible for this specific condition.
DM1 is caused by an expansion of CTG trinucleotide repeats in the 3' untranslated region (a non-coding region) of the DMPK gene. The expanded mRNA transcripts accumulate in the nucleus and sequester RNA-binding splicing factors.
This toxic gain-of-function at the RNA level leads to widespread defects in alternative splicing of various other mRNAs, explaining the diverse multisystemic nature of the disease (e.g., muscle, eye, and heart involvement).

Key Concept

Myotonic dystrophy type 1 is caused by a CTG trinucleotide repeat expansion in the non-coding region of the DMPK gene, leading to abnormal mRNA processing (spliceopathy).
Estimated Time:1m 30s
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Topics

Genetic and Molecular Mechanisms

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