TY - JOUR
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 D.
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.
N1 - Funding Information:
Funding MRK, MWL, JLC, MJH, SLM, SDD, TWF, KNO, SDS, MR, KEB, MCA, AL and MAZ are supported by National Institute of Health research grant 5 U54 HL096458-06 , funded by the Office of the Director, and supported by ORDR and NHLBI, NIH. MRK and MAZ are supported by National Institutes of Health grant 5 R01HL071798 . TWF is supported by R01 HL08265 and Children's Discovery Institute . KNO is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. JLC is supported by Clinical Innovator Award by Flight Attendant Medical Research Institute. HO is supported by a grant from the Deutsche Forschungsgemeinschaft (DFG Om 6/4, GRK1104, SFB592) . Resequencing was provided by the University of Washington, Department of Genome Sciences, under US Federal government contract number N01-HV-48194 from National Heart, Lung, and Blood Institute. This work was supported in part by grants RR00046, UL1 RR025747 and UL1 RR025780 from the National Center of Research Resources, NHLBI P01 HL034322, NIH and CFF R026-CR07 . This consortium, Genetic Disorders of Mucociliary Clearance is part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project was provided by grant 5 U54 HL096458-06 from the NHLBI and the NIH Office of Rare Diseases Research (ORDR) . The views expressed do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organisations imply endorsement by the U.S government.
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.
UR - https://www.scopus.com/pages/publications/84859823623
U2 - 10.1136/thoraxjnl-2011-200301
DO - 10.1136/thoraxjnl-2011-200301
M3 - Article
C2 - 22184204
AN - SCOPUS:84859823623
SN - 0040-6376
VL - 67
SP - 433
EP - 441
JO - Thorax
JF - Thorax
IS - 5
ER -