DNAH11 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder of motile cilia function characterized by chronic bronchiectasis, recurrent respiratory tract infections, and laterality defects including situs inversus totalis (PMID:12142464). The axonemal heavy chain dynein type 11 gene, DNAH11, encodes a β-type outer dynein arm motor protein critical for ciliary motility.

Biallelic pathogenic variants in DNAH11 have been reported in over 100 unrelated PCD probands across more than 50 families, consistent with autosomal recessive inheritance and multi-family segregation over two decades of studies; these include numerous loss-of-function alleles and missense changes disrupting motor function, accounting for a minority of PCD cases but a common cause of the normal-ultrastructure PCD subtype (PMID:12142464). In a Belgian cohort of 74 genetically confirmed PCD patients, 23 carried biallelic DNAH11 variants, predominantly compound heterozygous missense and frameshift changes, reinforcing the variant spectrum and recurrence of loss-of-function alleles (PMID:38602513).

Ciliary beat analysis and segregation studies have demonstrated clear co-segregation of DNAH11 variants with PCD phenotypes in multiple consanguineous and outbred pedigrees. Although specific segregation counts vary by report, the consistent autosomal recessive pattern and absence of pathogenic DNAH11 variants in healthy controls support causality.

Functional investigations using immunofluorescence microscopy and transmission electron microscopy tomography revealed that DNAH11 localizes exclusively to the proximal region of respiratory cilia; loss-of-function mutations result in subtle proximal outer dynein arm defects and a hyperkinetic ciliary beat pattern, mirroring patient hyperkinetic motility and normal ultrastructure phenotype (PMID:26909801). Murine models of Dnah11 loss recapitulate laterality defects and ciliary dysmotility, further supporting a hypomorphic to null mechanism.

No significant conflicting evidence has been reported; the association between DNAH11 and PCD remains robust across genetic, functional, and clinical studies.

Integration of genetic and functional data confirms that DNAH11 pathogenic variants cause autosomal recessive PCD, especially the normal-ultrastructure subtype. Genetic testing for DNAH11 is essential for accurate diagnosis, guiding management and genetic counseling. Key take-home: DNAH11 sequencing yields high diagnostic utility in PCD, particularly for patients with normal ciliary ultrastructure and hyperkinetic ciliary beating.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2002 • Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. PMID:12142464
• American journal of respiratory cell and molecular biology • 2016 • DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes. PMID:26909801
• Lung • 2024 • Genetic Spectrum and Clinical Characteristics of Patients with Primary Ciliary Dyskinesia: a Belgian Single Center Study. PMID:38602513

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