Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure

Michael R. Knowles, Margaret W. Leigh, Johnny L. Carson, Stephanie Davis, Sharon D. Dell, Thomas W. Ferkol, Kenneth N. Olivier, Scott D. Sagel, Margaret Rosenfeld, Kimberlie A. Burns, Susan L. Minnix, Michael C. Armstrong, Adriana Lori, Milan J. Hazucha, Niki T. Loges, Heike Olbrich, Anita Becker-Heck, Miriam Schmidts, Claudius Werner, Heymut OmranMaimoona A. Zariwala

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Rationale: Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11). Objectives: To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology. Methods: 82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease. Results: Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations. Conclusions: Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.

Original languageEnglish (US)
Pages (from-to)433-441
Number of pages9
JournalThorax
Volume67
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

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Kartagener Syndrome
Dyneins
Mutation
Cilia
Nose
Exons
Nitric Oxide
Situs Inversus
Phenotype
Bronchiectasis
Introns
Lung Diseases

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Knowles, M. R., Leigh, M. W., Carson, J. L., Davis, S., Dell, S. D., Ferkol, T. W., ... Zariwala, M. A. (2012). Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Thorax, 67(5), 433-441. https://doi.org/10.1136/thoraxjnl-2011-200301

Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. / Knowles, Michael R.; Leigh, Margaret W.; Carson, Johnny L.; Davis, Stephanie; Dell, Sharon D.; Ferkol, Thomas W.; Olivier, Kenneth N.; Sagel, Scott D.; Rosenfeld, Margaret; Burns, Kimberlie A.; Minnix, Susan L.; Armstrong, Michael C.; Lori, Adriana; Hazucha, Milan J.; Loges, Niki T.; Olbrich, Heike; Becker-Heck, Anita; Schmidts, Miriam; Werner, Claudius; Omran, Heymut; Zariwala, Maimoona A.

In: Thorax, Vol. 67, No. 5, 05.2012, p. 433-441.

Research output: Contribution to journalArticle

Knowles, MR, Leigh, MW, Carson, JL, Davis, S, Dell, SD, Ferkol, TW, Olivier, KN, Sagel, SD, Rosenfeld, M, Burns, KA, Minnix, SL, Armstrong, MC, Lori, A, Hazucha, MJ, Loges, NT, Olbrich, H, Becker-Heck, A, Schmidts, M, Werner, C, Omran, H & Zariwala, MA 2012, 'Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure', Thorax, vol. 67, no. 5, pp. 433-441. https://doi.org/10.1136/thoraxjnl-2011-200301
Knowles, Michael R. ; Leigh, Margaret W. ; Carson, Johnny L. ; Davis, Stephanie ; Dell, Sharon D. ; Ferkol, Thomas W. ; Olivier, Kenneth N. ; Sagel, Scott D. ; Rosenfeld, Margaret ; Burns, Kimberlie A. ; Minnix, Susan L. ; Armstrong, Michael C. ; Lori, Adriana ; Hazucha, Milan J. ; Loges, Niki T. ; Olbrich, Heike ; Becker-Heck, Anita ; Schmidts, Miriam ; Werner, Claudius ; Omran, Heymut ; Zariwala, Maimoona A. / Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. In: Thorax. 2012 ; Vol. 67, No. 5. pp. 433-441.
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title = "Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure",
abstract = "Rationale: Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11). Objectives: To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology. Methods: 82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease. Results: Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22{\%}) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69{\%}) were nonsense, insertion/deletion or loss-of-function splice-site mutations. Conclusions: Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.",
author = "Knowles, {Michael R.} and Leigh, {Margaret W.} and Carson, {Johnny L.} and Stephanie Davis and Dell, {Sharon D.} and Ferkol, {Thomas W.} and Olivier, {Kenneth N.} and Sagel, {Scott D.} and Margaret Rosenfeld and Burns, {Kimberlie A.} and Minnix, {Susan L.} and Armstrong, {Michael C.} and Adriana Lori and Hazucha, {Milan J.} and Loges, {Niki T.} and Heike Olbrich and Anita Becker-Heck and Miriam Schmidts and Claudius Werner and Heymut Omran and Zariwala, {Maimoona A.}",
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T1 - Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure

AU - Knowles, Michael R.

AU - Leigh, Margaret W.

AU - Carson, Johnny L.

AU - Davis, Stephanie

AU - Dell, Sharon D.

AU - Ferkol, Thomas W.

AU - Olivier, Kenneth N.

AU - Sagel, Scott D.

AU - Rosenfeld, Margaret

AU - Burns, Kimberlie A.

AU - Minnix, Susan L.

AU - Armstrong, Michael C.

AU - Lori, Adriana

AU - Hazucha, Milan J.

AU - Loges, Niki T.

AU - Olbrich, Heike

AU - Becker-Heck, Anita

AU - Schmidts, Miriam

AU - Werner, Claudius

AU - Omran, Heymut

AU - Zariwala, Maimoona A.

PY - 2012/5

Y1 - 2012/5

N2 - Rationale: Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11). Objectives: To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology. Methods: 82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease. Results: Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations. Conclusions: Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.

AB - Rationale: Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11). Objectives: To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology. Methods: 82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease. Results: Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations. Conclusions: Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.

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