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 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 journalArticle

78 Citations (Scopus)

Abstract

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
Volume189
Issue number6
DOIs
StatePublished - Mar 15 2014

Fingerprint

Kartagener Syndrome
Phenotype
Mutation
Exome
Cilia
Siblings
Nitric Oxide
Genotype
Nose Diseases
Bronchiectasis
Nose
Cough
Genes

Keywords

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

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. / Knowles, Michael R.; Ostrowski, Lawrence E.; Leigh, Margaret W.; Sears, Patrick R.; Davis, Stephanie; Wolf, Whitney E.; Hazucha, Milan J.; Carson, Johnny L.; Olivier, Kenneth N.; Sagel, Scott D.; Rosenfeld, Margaret; Ferkol, Thomas W.; Dell, Sharon D.; Milla, Carlos E.; Randell, Scott H.; Yin, Weining; Sannuti, Aruna; Metjian, Hilda M.; Noone, Peadar G.; Noone, Peter J.; Olson, Christina A.; Patrone, Michael V.; Dang, Hong; Lee, Hye Seung; Hurd, Toby W.; Gee, Heon Yung; Otto, Edgar A.; Halbritter, Jan; Kohl, Stefan; Kircher, Martin; Krischer, Jeffrey; Bamshad, Michael J.; Nickerson, Deborah A.; Hildebrandt, Friedhelm; Shendure, Jay; Zariwala, Maimoona A.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 189, No. 6, 15.03.2014, p. 707-717.

Research output: Contribution to journalArticle

Knowles, MR, Ostrowski, LE, Leigh, MW, Sears, PR, Davis, S, Wolf, WE, Hazucha, MJ, Carson, JL, Olivier, KN, Sagel, SD, Rosenfeld, M, Ferkol, TW, Dell, SD, Milla, CE, Randell, SH, Yin, W, Sannuti, A, Metjian, HM, Noone, PG, Noone, PJ, Olson, CA, Patrone, MV, Dang, H, Lee, HS, Hurd, TW, Gee, HY, Otto, EA, Halbritter, J, Kohl, S, Kircher, M, Krischer, J, Bamshad, MJ, Nickerson, DA, Hildebrandt, F, Shendure, J & Zariwala, MA 2014, 'Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype', American Journal of Respiratory and Critical Care Medicine, vol. 189, no. 6, pp. 707-717. https://doi.org/10.1164/rccm.201311-2047OC
Knowles, Michael R. ; Ostrowski, Lawrence E. ; Leigh, Margaret W. ; Sears, Patrick R. ; Davis, Stephanie ; Wolf, Whitney E. ; Hazucha, Milan J. ; Carson, Johnny L. ; Olivier, Kenneth N. ; Sagel, Scott D. ; Rosenfeld, Margaret ; Ferkol, Thomas W. ; Dell, Sharon D. ; Milla, Carlos E. ; Randell, Scott H. ; Yin, Weining ; Sannuti, Aruna ; Metjian, Hilda M. ; Noone, Peadar G. ; Noone, Peter J. ; Olson, Christina A. ; Patrone, Michael V. ; Dang, Hong ; Lee, Hye Seung ; Hurd, Toby W. ; Gee, Heon Yung ; Otto, Edgar A. ; Halbritter, Jan ; Kohl, Stefan ; Kircher, Martin ; Krischer, Jeffrey ; Bamshad, Michael J. ; Nickerson, Deborah A. ; Hildebrandt, Friedhelm ; Shendure, Jay ; Zariwala, Maimoona A. / Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 189, No. 6. pp. 707-717.
@article{53fdd0bbadcb438dab04015fe3af16ef,
title = "Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype",
abstract = "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.",
keywords = "Cilia, Ciliopathy, Exome sequencing, Kartagener syndrome, RSPH1",
author = "Knowles, {Michael R.} and Ostrowski, {Lawrence E.} and Leigh, {Margaret W.} and Sears, {Patrick R.} and Stephanie Davis and Wolf, {Whitney E.} and Hazucha, {Milan J.} and Carson, {Johnny L.} and Olivier, {Kenneth N.} and Sagel, {Scott D.} and Margaret Rosenfeld and Ferkol, {Thomas W.} and Dell, {Sharon D.} and Milla, {Carlos E.} and Randell, {Scott H.} and Weining Yin and Aruna Sannuti and Metjian, {Hilda M.} and Noone, {Peadar G.} and Noone, {Peter J.} and Olson, {Christina A.} and Patrone, {Michael V.} and Hong Dang and Lee, {Hye Seung} and Hurd, {Toby W.} and Gee, {Heon Yung} and Otto, {Edgar A.} and Jan Halbritter and Stefan Kohl and Martin Kircher and Jeffrey Krischer and Bamshad, {Michael J.} and Nickerson, {Deborah A.} and Friedhelm Hildebrandt and Jay Shendure and Zariwala, {Maimoona A.}",
year = "2014",
month = "3",
day = "15",
doi = "10.1164/rccm.201311-2047OC",
language = "English",
volume = "189",
pages = "707--717",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "6",

}

TY - JOUR

T1 - Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype

AU - Knowles, Michael R.

AU - Ostrowski, Lawrence E.

AU - Leigh, Margaret W.

AU - Sears, Patrick R.

AU - Davis, Stephanie

AU - Wolf, Whitney E.

AU - Hazucha, Milan J.

AU - Carson, Johnny L.

AU - Olivier, Kenneth N.

AU - Sagel, Scott D.

AU - Rosenfeld, Margaret

AU - Ferkol, Thomas W.

AU - Dell, Sharon D.

AU - Milla, Carlos E.

AU - Randell, Scott H.

AU - Yin, Weining

AU - Sannuti, Aruna

AU - Metjian, Hilda M.

AU - Noone, Peadar G.

AU - Noone, Peter J.

AU - Olson, Christina A.

AU - Patrone, Michael V.

AU - Dang, Hong

AU - Lee, Hye Seung

AU - Hurd, Toby W.

AU - Gee, Heon Yung

AU - Otto, Edgar A.

AU - Halbritter, Jan

AU - Kohl, Stefan

AU - Kircher, Martin

AU - Krischer, Jeffrey

AU - Bamshad, Michael J.

AU - Nickerson, Deborah A.

AU - Hildebrandt, Friedhelm

AU - Shendure, Jay

AU - Zariwala, Maimoona A.

PY - 2014/3/15

Y1 - 2014/3/15

N2 - 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.

AB - 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.

KW - Cilia

KW - Ciliopathy

KW - Exome sequencing

KW - Kartagener syndrome

KW - RSPH1

UR - http://www.scopus.com/inward/record.url?scp=84896534982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896534982&partnerID=8YFLogxK

U2 - 10.1164/rccm.201311-2047OC

DO - 10.1164/rccm.201311-2047OC

M3 - Article

C2 - 24568568

AN - SCOPUS:84896534982

VL - 189

SP - 707

EP - 717

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 6

ER -