Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD; MIM 242650) is an autosomal recessive disorder of ciliary dysfunction with extensive genetic heterogeneity. PCD is characterized by bronchiectasis and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome). We characterized the transcript and the genomic organization of the axonemal heavy chain dynein type 11 (DNAH11) gene, the human homologue of murine Dnah11 or lrd, which is mutated in the iv/iv mouse model with situs inversus. To assess the role of DNAH11, which maps on chromosome 7p21, we searched for mutations in the 82 exons of this gene in a patient with situs inversus totalis, and probable Kartagener syndrome associated with paternal uniparental disomy of chromosome 7 (patUPD7). We identified a homozygous nonsense mutation (R2852X) in the DNAH11 gene. This patient is remarkable because he is also homozygous for the F508del allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sequence analysis of the DNAH11 gene in an additional 6 selected PCD sibships that shared DNAH11 alleles revealed polymorphic variants and an R3004Q substitution in a conserved position that might be pathogenic. We conclude that mutations in the coding region of DNAH11 account for situs inversus totalis and probably a minority of cases of PCD.

Fig 1.

(A) DNAH11 gene. Chromosomal localization, genomic clones, and exon distribution shown as the output of the nix program (http://menu.hgmp.mrc.ac.uk/menu-bin/Nix/Nix.pl). Exons are numbered. Nucleotide numbers are shown in the thick green line. Clones corresponding to the nucleotide sequences are also shown. (B) Schematic representation of the domain structure of DNAH11 (not exactly to scale). P1–P4, the four P-loops; AAA1–AAA6, the six AAA modules; Helix1-MT-Helix2, the B-link that includes the microtubule binding domain. The positions of the R2852X mutation and the other amino acid substitutions found are shown. (C) DNA sequence chromatogram of exon 52 of DNAH11 showing homozygosity for the nonsense R2852X mutation. (D) Nuclear pedigree of patient C.C. with paternal UPD7 and schematic representation of portions of chromosome 7 with mutations in the CFTR and DNAH11 genes. The mutant alleles are shown with red symbols, and the normal alleles are shown with clear symbols.