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3 results on '"ABCA3 MUTATIONS"'

1. Ultrastructure of Lamellar Bodies in Congenital Surfactant Deficiency.

Author

Edwards, V., Cutz, E., Viero, S., Moore, A. M., and Nogee, L.

Subjects
*SURFACE active agents, *CLINICAL pathology, *BIOLOGICAL transport, *RESPIRATORY insufficiency, *BIOPSY, *DYSPLASIA, *PULMONARY fibrosis, *MICROSCOPY
Abstract

Congenital surfactant deficiency (CSD) is a newly identified neonatal lung disorder associated with a variety of molecular defects affecting surfactant synthesis and secretion in alveolar type II cells. The authors present ultrastructural findings of abnormal lamellar bodies in lung biopsies from 4 infants with CSD. All were term infants presenting shortly after birth with severe respiratory failure that was unresponsive to conventional therapy and all died within the first month of life. Lung biopsies were performed between 8 and 25 days of age. Biochemical and molecular studies in 2 unrelated male infants identified SP-B deficiency, one case with 121 ins 2 mutation and the second with a 209 + 4 A > G mutaion. Light microscopy in both cases showed features of alveolar proteinosis. Ultrastructurally, alveolar type II cells lacked mature lamellar bodies, and their cytoplasm contained numerous pleomorphic inclusions with membranous and vesicular structures not seen in normal type II cells. The other 2 infants were a pair of siblings in whom molecular studies identified mutations in ABCA3 transporter gene. Light microscopy showed features of acinar dysplasia and desquamative interstitial pneumonitis. TEM studies revealed absence of mature lamellar bodies in type II cells and instead showed a mixture of cytoplsamic electron-dense inclusions with concentric membranes and distinctive electron dense aggregates. The ultrastructual changes in alveolar type II cells correlated well with specific gene defect. In SP-B deficiency, the absence of mature lamellar bodies is consistent with the postulated role for this protein in the formation of lamellar bodies. The lack of mature lamellar bodies in the ABCA3 gene mutations is due to the dysfunction of this endogenous lipid transporter that targets surfactant lipid moieties to the lamellar bodies. The findings demonstrate the importance of TEM studies of lung biopsies from infants with CSD as it is a critical adjunct in the diagnosis of neonatal lung disease and in defining the underlying cellular defects. [ABSTRACT FROM AUTHOR]

Published
2005
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2. Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

Author

Donatella, Peca, Renata, Boldrini, Jan, Johannson, Joseph T, Shieh, Arianna, Citti, Stefania, Petrini, Teresa, Salerno, Salvatore, Cazzato, Raffaele, Testa, Francesco, Messina, Alfredo, Onofri, Giovanna, Cenacchi, Per, Westermark, Nicola, Ullmann, Nicola, Ullman, Paola, Cogo, Renato, Cutrera, Olivier, Danhaive, Peca, D, Boldrini, R, Johannson, J, Shieh, Jt, Citti, A, Petrini, S, Salerno, T, Cazzato, S, Testa, R, Messina, F, Onofri, A, Cenacchi, G, Westermark, P, Ullman, N, Cogo, P, Cutrera, R, and Danhaive, O

Subjects
Adult, Male, Neonatal respiratory distress syndrome, Pathology, medicine.medical_specialty, Heterozygote, ALVEOLAR PROTEINOSIS, Biopsy, Clinical Sciences, INTERSTITIAL PNEUMONIA, SFTPC, ABCA3, medicine.disease_cause, Article, FAMILIAL PULMONARY-FIBROSIS, Microscopy, Electron, Transmission, Genotype, Genetics, medicine, Humans, ABCA3 MUTATIONS, Child, Lung, Genetics (clinical), Surfactant homeostasis, TRANSGENIC MICE, Genetics & Heredity, Mutation, biology, Interstitial lung disease, Infant, Newborn, Surfactant protein C, surfactant protein C mutations, medicine.disease, Pulmonary Surfactant-Associated Protein C, Metabolism disorder, DEFICIENCY, GENE-MUTATIONS, RESPIRATORY-DISTRESS, BRICHOS DOMAIN, Phenotype, Immunology, biology.protein, Female, Lung Diseases, Interstitial, Corrigendum, Protein C
Abstract

© 2015 Macmillan Publishers Limited Genetic defects of surfactant metabolism are associated with a broad range of clinical manifestations, from neonatal respiratory distress syndrome to adult interstitial lung disease. Early therapies may improve symptoms but diagnosis is often delayed owing to phenotype and genotype variability. Our objective was to characterize the cellular/ultrastructural correlates of surfactant protein C (SP-C) mutations in children with idiopathic diffuse lung diseases. We sequenced SFTPC – the gene encoding SP-C – SFTPB and ABCA3, and analyzed morphology, ultrastructure and SP expression in lung tissue when available. We identified eight subjects who were heterozygous for SP-C mutations. Median age at onset and clinical course were variable. None of the mutations were located in the mature peptide-encoding region, but were either in the pro-protein BRICHOS or linker C-terminal domains. Although lung morphology was similar to other genetic surfactant metabolism disorders, electron microscopy studies showed specific anomalies, suggesting surfactant homeostasis disruption, plus trafficking defects in the four subjects with linker domain mutation and protein misfolding in the single BRICHOS mutation carrier in whom material was available. Immunolabeling studies showed increased proSP-C staining in all cases. In two cases, amyloid deposits could be identified. Immunochemistry and ultrastructural studies may be useful for diagnostic purposes and for genotype interpretation.European Journal of Human Genetics advance online publication, 18 March 2015; doi:10.1038/ejhg.2015.45.

Published
2015
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3. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis

Author

Steve D. Groshong, Philip L. Molyneaux, Williamson Z. Bradford, David McKean, Harold R. Collard, Dong Soon Kim, Janet Talbert, Lisa Lancaster, Keith P Smith, James E. Loyd, Kenneth B. Beckman, Mark P. Steele, Moisés Selman, Gunnar Gudmundsson, David A. Schwartz, Ravin N. Kidd, David A. Lynch, Wendi R. Mason, Gregory P. Cosgrove, Jerry Daniel, Kevin K. Brown, Joy D. Cogan, Mark Lathrop, Annie Pardo, Karl Kossen, Yingze Zhang, Elissa Murphy, Toby M. Maher, Christine Kim Garcia, Diana Zelenika, Dinesha Walek, Marvin I. Schwarz, Naftali Kaminski, Scott D. Seiwert, Helgi J Isaksson, Cheryl Markin, Brent S. Pedersen, Roland M. du Bois, James D. Crapo, Athol U. Wells, Paul J. Wolters, Weiming Zhang, Tasha E. Fingerlin, Anna L. Peljto, Kevin F. Gibson, Miriam F. Moffatt, Megan S. Devine, Elizabeth A. Regan, Yoichiro Kamatani, and Barry J. Make

Subjects
DNA repair, Gene Expression, Genome-wide association study, Biology, INTERSTITIAL PNEUMONIA, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Article, HAIR SYNDROME, 03 medical and health sciences, Idiopathic pulmonary fibrosis, PALMOPLANTAR KERATODERMA, 0302 clinical medicine, Gene Frequency, Polymorphism (computer science), RIGHT-VENTRICULAR DYSPLASIA/CARDIOMYOPATHY, Pulmonary fibrosis, Genetics, medicine, Chromosomes, Human, Humans, Genetic Predisposition to Disease, ABCA3 MUTATIONS, Idiopathic interstitial pneumonia, Gene, Allele frequency, Lung, 030304 developmental biology, Genetics & Heredity, 0303 health sciences, Science & Technology, Sequence Analysis, DNA, 11 Medical And Health Sciences, 06 Biological Sciences, medicine.disease, SURFACTANT PROTEIN-C, DESMOPLAKIN CAUSES, Idiopathic Pulmonary Fibrosis, 3. Good health, 030228 respiratory system, Genetic Loci, Case-Control Studies, SIGNALING PATHWAY, Life Sciences & Biomedicine, CELL-ADHESION, Genome-Wide Association Study, Developmental Biology
Abstract

We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. We confirmed association with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the chromosome 3q26 region near TERC, and identified 7 novel loci (PMeta = 2.4×10−8 to PMeta = 1.1×10−19). The novel loci include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15. Our results demonstrate that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic IIP.

Published
2013

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