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The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA

Johanna M Jank1, Esther M Maier1, Dunja D Reiβ1

  • 1Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.

Plos One
|April 11, 2014
PubMed

Insights

Newborn screening identifies medium-chain acyl-CoA dehydrogenase deficiency (MCADD) mutations. Fever exacerbates MCAD enzyme dysfunction, increasing decompensation risk. Aggressive fever reduction may be life-saving for MCADD patients.

Area of Science:

  • Biochemistry
  • Genetics
  • Molecular Biology

Background:

  • Expanded newborn screening programs have reduced mortality and morbidity in medium-chain acyl-CoA dehydrogenase deficiency (MCADD).
  • MCADD is caused by mutations in the ACADM gene, leading to a protein misfolding disease with loss-of-function.
  • Fever is a critical risk factor for metabolic decompensation in MCADD patients.

Purpose of the Study:

  • To analyze the structural consequences of eight ACADM missense mutations identified via newborn screening.
  • To link protein misfolding phenotypes to mutation sites and assess their impact on thermal stress.
  • To provide a systematic classification of conformational derangements for assessing clinical risk in MCADD patients.

Main Methods:

  • Comprehensive experimental setup to analyze structural consequences of eight ACADM missense mutations.
  • Assessment of protein conformation, thermal stability, and kinetic stability.
  • Evaluation of the impact of thermal stress on MCAD enzyme function.

Main Results:

  • The molecular phenotype in MCADD depends on the affected structural region, with the central β-domain being particularly susceptible to destabilization.
  • Mutations in the ACADM gene lower the temperature threshold for MCAD loss-of-function.
  • Increased temperature significantly elevates the risk of conformational derangement and enzyme dysfunction.

Conclusions:

  • Missense mutations in ACADM cause MCADD through protein misfolding and loss-of-function.
  • Thermal instability is a key factor in MCADD decompensation during fever episodes.
  • Early and aggressive antipyretic treatment is crucial for managing MCADD and preventing life-threatening complications.

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