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An essential role of intestinal cell kinase in lung development is linked to the perinatal lethality of human ECO syndrome
Author(s) -
Tong Yixin,
Park So Hyun,
Wu Di,
Xu Wenhao,
Guillot Stacey J.,
Jin Li,
Li Xudong,
Wang Yalin,
Lin ChyuanSheng,
Fu Zheng
Publication year - 2017
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12644
Subject(s) - cilium , phenotype , biology , lung , microbiology and biotechnology , mesenchymal stem cell , mutation , morphogenesis , cancer research , endocrinology , medicine , genetics , gene
Human endocrine‐cerebro‐osteodysplasia ( ECO ) syndrome, caused by the loss‐of‐function mutation R272Q in the intestinal cell kinase ( ICK ) gene, is a neonatal‐lethal developmental disorder. To elucidate the molecular basis of ECO syndrome, we constructed an Ick R272Q knock‐in mouse model that recapitulates ECO pathological phenotypes. Newborns bearing Ick R272Q homozygous mutations die at birth due to respiratory distress. Ick mutant lungs exhibit not only impaired branching morphogenesis associated with reduced mesenchymal proliferation but also significant airspace deficiency in primitive alveoli concomitant with abnormal interstitial mesenchymal differentiation. ICK dysfunction induces elongated primary cilia and perturbs ciliary Hedgehog signaling and autophagy during lung sacculation. Our study identifies an essential role for ICK in lung development and advances the mechanistic understanding of ECO syndrome.