title: Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa.
abstract: Mutations involving elastic tissue proteins result in a broad spectrum of phenotypes affecting skin, skeleton, ocular and vascular structures, including tortuous blood vessels and cutis laxa. Here we report on a female newborn with apparently long fingers, aortic aneurysm, tortuous pulmonary arteries and mild generalized lax skin. She died at 27 days of age due to severe respiratory distress and inoperable systemic vascular abnormalities. Skin biopsy showed marked paucity and fragmentation of elastic fibers and autopsy revealed occlusion of the pulmonary artery. DNA analysis identified compound heterozygous mutations ((c.835C > T (p.R279C)/c.1070_1073dupCCGC) in fibulin-4, a recently recognized elastic fiber associated protein. Analyses of dermal fibroblasts from the patient indicated that fibulin-4 mRNAs with the 4-bp duplication transcribed from one allele are probably subject to nonsense-mediated decay, whereas synthesis and secretion of the missense R279C fibulin-4 protein from the other allele is severely impaired. Immunostaining demonstrated a total absence of fibulin-4 fibers in the extracellular matrix deposited by the patient's fibroblasts. Our studies provide evidence that deficiency in fibulin-4 leads to a perinatal lethal condition associated with elastic tissue abnormalities.
authors.affiliation: Division of Genetics, Endocrinology & Metabolism, Department of Pediatrics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA. mdasouki@kumc.edu
authors.forename: Majed
authors.initials: M
authors.lastname: Dasouki
authors.forename: Dessislava
authors.initials: D
authors.lastname: Markova
authors.forename: Robert
authors.initials: R
authors.lastname: Garola
authors.forename: Takako
authors.initials: T
authors.lastname: Sasaki
authors.forename: Noe L
authors.initials: NL
authors.lastname: Charbonneau
authors.forename: Lynn Y
authors.initials: LY
authors.lastname: Sakai
authors.forename: Mon-Li
authors.initials: ML
authors.lastname: Chu
mesh_terms: D000015:Abnormalities, Multiple; D001014:Aortic Aneurysm / Q000209:etiology / Q000235:genetics*; D054119:Arachnodactyly / Q000209:etiology / Q000235:genetics*; D001157:Arterial Occlusive Diseases / Q000209:etiology / Q000235:genetics*; D003483:Cutis Laxa / Q000209:etiology / Q000235:genetics*; D004547:Elastic Tissue / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D011651:Pulmonary Artery
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins