Figure 1.

Recessive Loss-of-Function Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry

(A) The chest X-ray radiograph of PCD-affected individual OP-2334 II2 depicts situs inversus totalis. The computed tomography scan of OP-2334 II2 shows chronic airway disease with bronchiectasis in the middle lobe and mucus plugging.

(B) In situ hybridization analyses of wild-type 8.25 dpc (days post-coitum) mouse embryos reveal expression of 9230110C19Rik (C11orf70 ortholog) exclusively at the left/right organizer (frontal view; asterisks in the ventral position of the left/right organizer). By contrast, the negative control utilizing the sense probe does not show any staining.

(C) Schematic presentation of chromosome 11 and the exon-intron structure of C11orf70 with untranslated (gray) and translated (white) regions. The positions of the three identified mutations in the five unrelated families are indicated by red lines.

(D) Protein model of C11orf70 with the domain of unknown function 4498 (DUF 4498) and the predicted truncated proteins as consequences of the three C11orf70 loss-of-function mutations.

(E) Differentiation-specific and tissue-specific expression profiles of known genes encoding proteins involved in outer- and inner-dynein-arm assembly and GAPDH as a housekeeping gene. Raw RNA-seq data were normalized against PPIH (peptidylprolyl isomerase H). The preassembly-factor genes have the strongest expression in native material of nasal-brushing biopsies. Comparable expression profiles are observed in ALI-cultured nasal epithelial cells and in nasal-brushing biopsies. EBV cells (immortalized lymphocytes) and blood cells show no or weak expression of genes encoding cytoplasmic dynein assembly factors. GAPDH shows a high expression in all analyzed tissues. We performed two independent experiments with samples from five control individuals (samples 1–5).