TY - JOUR
T1 - Mutations in LTBP4 Cause a Syndrome of Impaired Pulmonary, Gastrointestinal, Genitourinary, Musculoskeletal, and Dermal Development
AU - Urban, Zsolt
AU - Hucthagowder, Vishwanathan
AU - Schürmann, Nura
AU - Todorovic, Vesna
AU - Zilberberg, Lior
AU - Choi, Jiwon
AU - Sens, Carla
AU - Brown, Chester W.
AU - Clark, Robin D.
AU - Holland, Kristen E.
AU - Marble, Michael
AU - Sakai, Lynn Y.
AU - Dabovic, Branka
AU - Rifkin, Daniel B.
AU - Davis, Elaine C.
N1 - Funding Information:
We thank the patients and their family members for participating in the study. We are also grateful to James Southern for providing pathological materials and to Barbara Mordue and Subhadra Ramanathan for clinical information and images. This study was funded in part by U.S. National Institutes of Health grants HL084922 (Z.U.), CA034282 (D.B.R.), and AR49698 (D.B.R.); March of Dimes grant 1-FY09-33 (Z.U.); Phillip Morris USA Inc. (D.B.R.), and Canadian Institutes of Health grant MOP86713 (E.C.D.). E.C.D. is a Canada Research Chair.
Funding Information:
The subjects of this study participated after giving their informed consent. This study was approved by the Human Research Protection Office (institutional review board) of the Washington University School of Medicine. Tissue samples were collected as skin biopsies or as autopsy material. Normal control tissue samples were provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute. Other investigators may have received samples from the same subjects.
PY - 2009/11/13
Y1 - 2009/11/13
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2009.09.013
DO - 10.1016/j.ajhg.2009.09.013
M3 - Article
C2 - 19836010
AN - SCOPUS:71849092773
SN - 0002-9297
VL - 85
SP - 593
EP - 605
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -