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Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing

Jing Cheng1, Yuhua Zhu, Sudan He

  • 1Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.

American Journal of Human Genetics
|July 5, 2011
PubMed

Insights

A SMAC/DIABLO gene mutation causes dominant progressive hearing loss (DFNA64). This mutation leads to mitochondrial dysfunction in inner ear hair cells, impacting hearing.

Area of Science:

  • Genetics
  • Cell Biology
  • Otolaryngology

Background:

  • SMAC/DIABLO is a mitochondrial protein crucial for apoptosis, counteracting inhibitor of apoptosis proteins (IAPs).
  • Progressive nonsyndromic hearing loss is a heterogeneous group of genetic disorders affecting auditory function.

Observation:

  • A novel heterozygous SMAC/DIABLO mutation (c.377C>T, p.Ser126Leu) was identified in a Chinese family with dominant progressive hearing loss (DFNA64).
  • SMAC/DIABLO shows high expression in embryonic ears and is concentrated in developing mouse inner ear hair cells.

Findings:

  • The identified SMAC/DIABLO(S71L) mutant retains proapoptotic function but induces degradation of both wild-type and mutant SMAC/DIABLO.
  • The mutant SMAC/DIABLO(S71L) compromises mitochondrial membrane potential, making them vulnerable to calcium-induced damage.

Implications:

  • This study identifies SMAC/DIABLO as a causative gene for DFNA64, a form of dominant progressive hearing loss.
  • Mutant SMAC/DIABLO(S71L) may lead to hearing impairment through mitochondrial dysfunction in inner ear hair cells.
  • This discovery opens new avenues for understanding the molecular mechanisms underlying genetic hearing loss.

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