Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development.
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.
Urban
Zsolt
Z
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA. urban_z@kids.wustl.edu
Hucthagowder
Vishwanathan
V
Schürmann
Nura
N
Todorovic
Vesna
V
Zilberberg
Lior
L
Choi
Jiwon
J
Sens
Carla
C
Brown
Chester W
CW
Clark
Robin D
RD
Holland
Kristen E
KE
Marble
Michael
M
Sakai
Lynn Y
LY
Dabovic
Branka
B
Rifkin
Daniel B
DB
Davis
Elaine C
EC
D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D020405:Dermis / Q000002:abnormalities* / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000002:abnormalities*; D053779:Latent TGF-beta Binding Proteins / Q000737:chemistry / Q000235:genetics*; D008168:Lung / Q000002:abnormalities* / Q000378:metabolism; D008297:Male; D009141:Musculoskeletal System; D009154:Mutation; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012867:Skin / Q000166:cytology; D013577:Syndrome; D014551:Urinary Tract / Q000002:abnormalities* / Q000378:metabolism
D017077:Culture Media, Conditioned; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; D012333:RNA, Messenger; D004247:DNA