In situ structure of the human ciliary transition zone links linker defects to primary ciliary dyskinesia
The ciliary transition zone (TZ) regulates ciliary proteome composition, yet its molecular architecture, protein content, and contribution to motile ciliopathies remain poorly defined. We applied in situ cryo-electron tomography and subtomogram averaging to human multiciliated epithelial cells. This approach resolved TZ-specific doublet microtubules at subnanometer resolution and identified nine constituent proteins. We identified that ECT2L and DZANK1 form the major linker complexes between adjacent TZ doublet microtubules. Biallelic loss-of-function variants in either gene cause primary ciliary dyskinesia. ECT2L and DZANK1 deficiency disrupted TZ architecture, caused microtubular abnormalities and abnormal bulbous ciliary tips, and impaired mucociliary clearance. These findings establish a direct genetic link between TZ defects and human motile ciliopathy, and illustrate how in situ structural biology can uncover mechanisms of human disease.
Authors
- Heymut Omran (ORCID: https://orcid.org/0000-0003-0282-6765)
- Andrew Berical (ORCID: https://orcid.org/0000-0002-0818-0259)
- Dario Prais (ORCID: https://orcid.org/0000-0002-4165-0144)
- Huda Mussaffi (ORCID: https://orcid.org/0000-0001-8840-5958)
- Kai Wohlgemuth (ORCID: https://orcid.org/0000-0003-4092-0664)
- Alan Brown (ORCID: https://orcid.org/0000-0002-0021-0476)
- Virginie Hamel (ORCID: https://orcid.org/0000-0001-5092-2343)
- Sivagurunathan Sutharsan (ORCID: https://orcid.org/0000-0003-4069-4900)
- Sven M. Lange (ORCID: https://orcid.org/0000-0002-6011-8647)
- Finn Hawkins (ORCID: https://orcid.org/0000-0002-2246-6448)
- Paul Guichard (ORCID: https://orcid.org/0000-0002-0363-1049)
- Sachiko Homma (ORCID: https://orcid.org/0000-0001-6563-8521)
- Joel Anderson (ORCID: https://orcid.org/0000-0002-1179-717X)
- Johanna Raidt (ORCID: https://orcid.org/0000-0002-1571-2647)
- Diana Bracht (ORCID: https://orcid.org/0000-0002-2151-038X)
- Haixia Zhou (ORCID: https://orcid.org/0000-0002-9676-6267)
- Marine Brunet (ORCID: https://orcid.org/0000-0001-7878-3832)
- Cynthia Rieck
- Jürgen Klingauf
- Victoria Dunphy
- Heike Olbrich
- Lea Terbeck (ORCID: https://orcid.org/0009-0009-1275-1454)
Institutions
- Boston University (US)
- University of Geneva (CH)
- Boston Medical Center (US)
- Harvard University (US)
- University of Münster (DE)
- Ruhrlandklinik (DE)
- University Hospital Münster (DE)
- Schneider Children's Medical Center (IL)
- Boston VA Research Institute (US)
Publication Details
- Journal
- Science
- Published
- 2026-09-10
- DOI
- https://doi.org/10.1126/science.aei5957
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00