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Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia

M Leigh Anne Daniels1, Margaret W Leigh, Stephanie D Davis

  • 1Department of Medicine, UNC School of Medicine, Chapel Hill, North Carolina.

Human Mutation
|June 26, 2013
PubMed

Insights

A novel splice-site mutation in RSPH4A causes primary ciliary dyskinesia (PCD) in Hispanic individuals from Puerto Rico. This common founder mutation, c.921+3_6delAAGT, leads to ciliary dysfunction without situs abnormalities.

Area of Science:

  • Genetics
  • Respiratory Medicine
  • Cell Biology

Background:

  • Primary ciliary dyskinesia (PCD) is a rare genetic disorder causing chronic oto-sino-pulmonary disease due to ciliary dysfunction.
  • Traditional diagnosis relies on electron microscopy for ciliary ultrastructure, but genetic testing is advancing diagnostic capabilities.
  • Mutations in radial spoke proteins are linked to PCD with central apparatus defects.

Purpose of the Study:

  • To identify novel genetic causes of primary ciliary dyskinesia (PCD).
  • To characterize a specific splice-site mutation in the RSPH4A gene.
  • To investigate the prevalence and origin of this mutation in a specific population.

Main Methods:

  • Genetic analysis to identify mutations in PCD patients.
  • Functional studies including ciliary ultrastructural analysis, beat frequency, and waveform measurements.
  • Transcript analysis to confirm loss-of-function.

Main Results:

  • A novel splice-site mutation, c.921+3_6delAAGT, was identified in the RSPH4A gene in nine individuals with PCD from seven families.
  • This mutation leads to a premature translation termination signal and confirmed loss-of-function.
  • All affected individuals were Hispanic with Puerto Rican ancestry, indicating a founder mutation common in this population and associated with PCD without situs abnormalities.

Conclusions:

  • The c.921+3_6delAAGT splice-site mutation in RSPH4A is a significant cause of primary ciliary dyskinesia (PCD) in individuals of Puerto Rican descent.
  • This mutation represents a founder effect and is linked to PCD phenotypes lacking situs abnormalities.
  • Genetic testing for this specific mutation can aid in diagnosing PCD in at-risk populations.

Keywords:
Kartagener syndromeRSPH4Aciliasequencing

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