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.

• Authors: Michael R Knowles, Margaret W Leigh, Johnny L Carson, Stephanie D 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 Omran, Maimoona A Zariwala, Genetic Disorders of Mucociliary Clearance Consortium
• Journal: Thorax (Thorax) Vol. 67 Issue 5 Pg. 433-41 (May 2012) ISSN: 1468-3296 [Electronic] England
• PMID: 22184204 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Axonemal Dyneins
• DNAH11 protein, human

Topics

• Adolescent
• Adult
• Axonemal Dyneins (genetics)
• Child
• Child, Preschool
• Cilia (ultrastructure)
• Ciliary Motility Disorders (diagnosis, genetics, pathology)
• Female
• Genotype
• Humans
• Infant
• Male
• Mutation
• Pedigree
• Phenotype
• Polymorphism, Genetic
• Reverse Transcriptase Polymerase Chain Reaction
• Young Adult