Mutations in LTBP4 Cause a Syndrome of Impaired Pulmonary, Gastrointestinal, Genitourinary, Musculoskeletal, and Dermal Development

Zsolt Urban, Vishwanathan Hucthagowder, Nura Schürmann, Vesna Todorovic, Lior Zilberberg, Jiwon Choi, Carla Sens, Chester W. Brown, Robin D. Clark, Kristen E. Holland, Michael Marble, Lynn Sakai, Branka Dabovic, Daniel B. Rifkin, Elaine C. Davis

Research output: Contribution to journalArticle

75 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)593-605
Number of pages13
JournalAmerican Journal of Human Genetics
Volume85
Issue number5
DOIs
StatePublished - Nov 13 2009

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Musculoskeletal Development
Transforming Growth Factors
Carrier Proteins
Lung
Skin
Mutation
Diverticulum
Extracellular Matrix
Cutis Laxa
Tracheomalacia
Joint Instability
Patent Foramen Ovale
Diaphragmatic Hernia
Elastic Tissue
Forehead
Pulmonary Atelectasis
Hydronephrosis
Urinary Tract
Respiratory Insufficiency
Pathologic Constriction

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mutations in LTBP4 Cause a Syndrome of Impaired Pulmonary, Gastrointestinal, Genitourinary, Musculoskeletal, and Dermal Development. / Urban, Zsolt; Hucthagowder, Vishwanathan; Schürmann, Nura; Todorovic, Vesna; Zilberberg, Lior; Choi, Jiwon; Sens, Carla; Brown, Chester W.; Clark, Robin D.; Holland, Kristen E.; Marble, Michael; Sakai, Lynn; Dabovic, Branka; Rifkin, Daniel B.; Davis, Elaine C.

In: American Journal of Human Genetics, Vol. 85, No. 5, 13.11.2009, p. 593-605.

Research output: Contribution to journalArticle

Urban, Z, Hucthagowder, V, Schürmann, N, Todorovic, V, Zilberberg, L, Choi, J, Sens, C, Brown, CW, Clark, RD, Holland, KE, Marble, M, Sakai, L, Dabovic, B, Rifkin, DB & Davis, EC 2009, 'Mutations in LTBP4 Cause a Syndrome of Impaired Pulmonary, Gastrointestinal, Genitourinary, Musculoskeletal, and Dermal Development', American Journal of Human Genetics, vol. 85, no. 5, pp. 593-605. https://doi.org/10.1016/j.ajhg.2009.09.013
Urban, Zsolt ; Hucthagowder, Vishwanathan ; Schürmann, Nura ; Todorovic, Vesna ; Zilberberg, Lior ; Choi, Jiwon ; Sens, Carla ; Brown, Chester W. ; Clark, Robin D. ; Holland, Kristen E. ; Marble, Michael ; Sakai, Lynn ; Dabovic, Branka ; Rifkin, Daniel B. ; Davis, Elaine C. / Mutations in LTBP4 Cause a Syndrome of Impaired Pulmonary, Gastrointestinal, Genitourinary, Musculoskeletal, and Dermal Development. In: American Journal of Human Genetics. 2009 ; Vol. 85, No. 5. pp. 593-605.
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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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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

AU - Dabovic, Branka

AU - Rifkin, Daniel B.

AU - Davis, Elaine C.

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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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