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

University of North Carolina, Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, CB# 7248, 7123 Thurston-Bowles Bldg, Chapel Hill, NC 27599-7248, USA.
Thorax (Impact Factor: 8.29). 12/2011; 67(5):433-41. DOI: 10.1136/thoraxjnl-2011-200301
Source: PubMed


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).
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.
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.
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.
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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Available from: Heymut Omran, Nov 09, 2015
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    • "One of the patients had Kartagener syndrome. Knowles et al. [34] sequenced DNAH11 in patients with a PCD clinical phenotype without a known genetic etiology and found that 69% had nonsense, insertion/deletion or loss of function splice site mutation and 22% had biallelic mutations in DNAH11. "
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    ABSTRACT: A 20 year old male was initially diagnosed suffering from Primary ciliary dyskinesia with symptoms of bronchiectasis, severe frontal, maxillary and ethmoid sinus disease. At the age of 20, the patient was also diagnosed with Myelodysplastic syndrome requiring Bone marrow transplant due to the advanced stage at time of presentation. Primary ciliary dyskinesia and Myelodsyplastic syndrome are both rare clinical conditions found in the general population, especially in young adults. This rare combination of disorders has never been reported in literature to the best of the author's knowledge. The presence of an advanced cancer and a genetic abnormality due to two deletions occurring in two arms of the same chromosome can be explained on the base of chromothripsis. A number of evidences have been published in the literature, about multiple deletions in chromosome 5 and advanced stages of MDS being associated with chromothripsis however this is the first case report on two deletions in chromosome 7 giving rise to two different clinical entities requiring multiple modes of management.
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    • "One of the strengths of our study is population size. A group of patients with PCD and NU has also been described by Knowles et al. [16], but this study focused on genetic diagnosis. "
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    • "More recently, mutations in several genes coding for several cytoplasmic proteins not found in the axoneme have been linked to PCD. These proteins are presumed to have roles in cilia assembly or protein transport, and mutations lead to ultrastructural abnormalities: HEATR2, DNAAF1, DNAAF2, DNAAF3, CCDC103, LRRC6, and CCDC114 (30, 42-44, 50-68). Little is known about most of these proteins, but their association with PCD has contributed to advances in our knowledge of cilia biogenesis. "
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