A 32-year-old man presents with progressive hand weakness, difficulty releasing a doorknob, and bilateral ptosis with temporal wasting. Examination reveals grip myotonia on handshake and percussion myotonia of the thenar eminence. Slit-lamp examination shows posterior subcapsular 'Christmas-tree' cataracts. ECG demonstrates first-degree AV block. Genetic testing reveals a heterozygous CTG repeat expansion (650 repeats) in the 3' UTR of the DMPK gene on the structure marked **A**. Which of the following best explains the pathogenic mechanism of this disorder?

Question

Accepted Answer

B. RNA toxic gain-of-function with sequestration of MBNL1 splicing factors causing missplicing of CLCN1, INSR, and cardiac troponin T. ## Why RNA toxic gain-of-function with sequestration of MBNL1 splicing factors is right

The structure marked **A** is chromosome 19q13.3 containing the DMPK gene with a CTG repeat expansion (650 repeats in this case). The pathogenic mechanism of myotonic dystrophy type 1 is NOT loss of DMPK protein function, but rather a toxic gain-of-function at the RNA level. The expanded CUG-containing transcripts form nuclear foci that sequester MBNL1 (muscleblind-like 1) splicing factors, preventing normal splicing of multiple genes including CLCN1 (chloride channel, causing myotonia), INSR (insulin receptor, causing insulin resistance), and cardiac troponin T (causing conduction disease). This mechanism directly explains the multisystem phenotype observed in this patient: myotonia (CLCN1 missplicing), cardiac conduction block (troponin T missplicing), and insulin resistance (INSR missplicing). This is the established molecular pathogenesis described in Harrison 21e Ch 441 and Bird GeneReviews DM1 2023.

## Why each distractor is wrong

- **Loss-of-function mutation in FMRP protein**: This describes fragile X syndrome, caused by CGG repeat expansion in FMR1 on chromosome Xq27.3 (marked **B** in the diagram), not myotonic dystrophy. FMRP loss causes intellectual disability and autism spectrum features, not myotonia or cardiac conduction disease.

- **Trinucleotide repeat expansion in huntingtin gene**: This describes Huntington disease, caused by CAG repeat expansion in HTT on chromosome 4p16.3 (marked **C** in the diagram). Huntington disease presents with chorea, psychiatric symptoms, and cognitive decline, not myotonia, cataracts, or conduction disease.

- **Frataxin protein deficiency**: This describes Friedreich ataxia, caused by GAA repeat expansion in FXN on chromosome 9q21 (marked **D** in the diagram). Friedreich ataxia presents with progressive ataxia, cardiomyopathy, and diabetes, but not myotonia or the characteristic facial features of DM1.

**High-Yield:** Myotonic dystrophy type 1 is a toxic RNA gain-of-function disease (not a loss-of-function), with MBNL1 sequestration causing widespread missplicing—this distinguishes it mechanistically from other trinucleotide repeat disorders and explains its multisystem phenotype.

[cite: Harrison 21e Ch 441; Bird GeneReviews DM1 2023]

Answer

A. Loss-of-function mutation in the FMRP protein leading to impaired synaptic plasticity and cognitive decline

Answer

C. Frataxin protein deficiency resulting in mitochondrial iron accumulation and progressive spinocerebellar ataxia

Answer

D. Trinucleotide repeat expansion in the huntingtin gene causing neuronal aggregation and selective striatal degeneration

Explanation

Why RNA toxic gain-of-function with sequestration of MBNL1 splicing factors is right

Why each distractor is wrong

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