Respiratory motile cilia dysfunction in a patient with cranioectodermal dysplasia.
Ciliopathies such as cranioectodermal dysplasia, Sensenbrenner syndrome, short-rib polydactyly, and Jeune syndrome are associated with respiratory complications arising from rib cage dysplasia. While such ciliopathies have been demonstrated to involve primary cilia defects, we show motile cilia dysfunction in the airway of a patient diagnosed with cranioectodermal dysplasia. While this patient had mild thoracic dystrophy not requiring surgical treatment, there was nevertheless newborn respiratory distress, restrictive airway disease with possible obstructive airway involvement, repeated respiratory infections, and atelectasis. High-resolution videomicroscopy of nasal epithelial biopsy showed immotile/dyskinetic cilia and nasal nitric oxide was reduced, both of which are characteristics of primary ciliary dyskinesia, a sinopulmonary disease associated with mucociliary clearance defects due to motile cilia dysfunction in the airway. Exome sequencing analysis of this patient identified compound heterozygous mutations in WDR35, but no mutations in any of the 30 known primary ciliary dyskinesia genes or other cilia-related genes. Given that WDR35 is only known to be required for primary cilia function, we carried out WDR35 siRNA knockdown in human respiratory epithelia to assess the role of WDR35 in motile cilia function. This showed WDR35 deficiency disrupted ciliogenesis in the airway, indicating WDR35 is also required for formation of motile cilia. Together, these findings suggest patients with WDR35 mutations have an airway mucociliary clearance defect masked by their restrictive airway disease.
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
You
Y
Li
Division of Pulmonary Medicine, Allergy & Immunology, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Andrea S
AS
Garrod
Division of Medical Genetics, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Suneeta
S
Madan-Khetarpal
Division of Medical Genetics, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Gayathri
G
Sreedher
Division of Medical Genetics, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Medical Genetics, Baylor College of Medicine, Houston, Texas.
Marianne
M
McGuire
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Hisato
H
Yagi
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Nikolai T
NT
Klena
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
George C
GC
Gabriel
Omar
O
Khalifa
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Maliha
M
Zahid
Department of Pediatric Radiology, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Ashok
A
Panigrahy
Division of Pulmonary Medicine, Allergy & Immunology, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Daniel J
DJ
Weiner
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Cecilia W
CW
Lo
D001842:Bone and Bones / Q000002:abnormalities*; D002648:Child; D002923:Cilia / Q000235:genetics*; D003398:Craniosynostoses / Q000235:genetics*; D003598:Cytoskeletal Proteins; D004476:Ectodermal Dysplasia / Q000235:genetics*; D053823:Hedgehog Proteins; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009154:Mutation / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012140:Respiratory Tract Diseases / Q000235:genetics*
D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C558596:WDR35 protein, human
Sensenbrenner syndrome; WDR35; cranioectodermal dysplasia; motile cilia dysfunction