Faculty Collaboration Database

Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Am J Hum Genet 2009 Nov;85(5):593-605

Date

10/20/2009

Pubmed ID

19836010

Pubmed Central ID

PMC2775835

DOI

10.1016/j.ajhg.2009.09.013

Scopus ID

2-s2.0-71849092773 (requires institutional sign-in at Scopus site)   120 Citations

Abstract

We report recessive mutations in the gene for the latent transforming growth factor-beta 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-beta (TGF-beta) 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-beta signaling and ECM assembly is essential for proper development and is achieved in multiple human organ systems by multifunctional proteins such as LTBP4.

Author List

Urban Z, Hucthagowder V, Schürmann N, Todorovic V, Zilberberg L, Choi J, Sens C, Brown CW, Clark RD, Holland KE, Marble M, Sakai LY, Dabovic B, Rifkin DB, Davis EC

Author

Kristen E. Holland MD Associate Professor in the Dermatology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cells, Cultured
Child
Child, Preschool
Coculture Techniques
Culture Media, Conditioned
DNA
Dermis
Female
Fibroblasts
Gene Expression Regulation, Developmental
Heterozygote
Homozygote
Humans
Immunohistochemistry
Infant
Intestinal Mucosa
Intestines
Latent TGF-beta Binding Proteins
Lung
Male
Musculoskeletal System
Mutation
Protein Structure, Tertiary
RNA, Messenger
Sequence Analysis, DNA
Skin
Syndrome
Urinary Tract