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Mutations in LTBP4 Cause a Syndrome of Impaired Pulmonary, Gastrointestinal, Genitourinary, Musculoskeletal, and Dermal Development |
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| Authors: | Zsolt Urban Vishwanathan Hucthagowder Vesna Todorovic Jiwon Choi Chester W Brown Robin D Clark Michael Marble Lynn Y Sakai Daniel B Rifkin Elaine C Davis |
| Institution: | 1 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA 2 Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA 3 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA 4 Department of Cell Biology, New York University Langone School of Medicine, New York, NY 10016, USA 5 Department of Medicine, New York University Langone School of Medicine, New York, NY 10016, USA 6 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada 7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 8 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA 9 Department of Pediatrics, Loma Linda School of Medicine, Loma Linda, CA 92354, USA 10 Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI 53226, USA 11 Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70118, USA 12 Children's Hospital of New Orleans, New Orleans, LA 70118, USA 13 Department of Biochemistry and Molecular Biology, Shriners Hospital for Children, Oregon Health & Science University, Portland, OR 97239, USA |
| Abstract: | We report recessive mutations in the gene for the latent transforming growth factor-β binding protein 4 (LTBP4) in four unrelated patients with a human syndrome disrupting pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All patients had severe respiratory distress, with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Three of the four patients died of respiratory failure. Cardiovascular lesions were mild, limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis, enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide fontanelles. All patients had cutis laxa. Four of the five identified LTBP4 mutations led to premature termination of translation and destabilization of the LTBP4 mRNA. Impaired synthesis and lack of deposition of LTBP4 into the extracellular matrix (ECM) caused increased transforming growth factor-β (TGF-β) activity in cultured fibroblasts and defective elastic fiber assembly in all tissues affected by the disease. These molecular defects were associated with blocked alveolarization and airway collapse in the lung. Our results show that coupling of TGF-β signaling and ECM assembly is essential for proper development and is achieved in multiple human organ systems by multifunctional proteins such as LTBP4. |
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