Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype

Michael R. Knowles, Lawrence E. Ostrowski, Margaret W. Leigh, Patrick R. Sears, Stephanie D. Davis, Whitney E. Wolf, Milan J. Hazucha, Johnny L. Carson, Kenneth N. Olivier, Scott D. Sagel, Margaret Rosenfeld, Thomas W. Ferkol, Sharon D. Dell, Carlos E. Milla, Scott H. Randell, Weining Yin, Aruna Sannuti, Hilda M. Metjian, Peadar G. Noone, Peter J. NooneChristina A. Olson, Michael V. Patrone, Hong Dang, Hye Seung Lee, Toby W. Hurd, Heon Yung Gee, Edgar A. Otto, Jan Halbritter, Stefan Kohl, Martin Kircher, Jeffrey Krischer, Michael J. Bamshad, Deborah A. Nickerson, Friedhelm Hildebrandt, Jay Shendure, Maimoona A. Zariwala

Research output: Contribution to journalArticlepeer-review

174 Scopus citations


Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD. Objectives: To identify disease-causingmutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD. Methods: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis. Measurements and Main Results: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P , 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.16Hz at 258C), but an abnormal, circular beat pattern. Conclusions: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.

Original languageEnglish
Pages (from-to)707-717
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Issue number6
StatePublished - Mar 15 2014


  • Cilia
  • Ciliopathy
  • Exome sequencing
  • Kartagener syndrome
  • RSPH1


Dive into the research topics of 'Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype'. Together they form a unique fingerprint.

Cite this