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      Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations

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          Abstract

          Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis.

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          Most cited references 38

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          Transcriptional control of lung morphogenesis.

          The vertebrate lung consists of multiple cell types that are derived primarily from endodermal and mesodermal compartments of the early embryo. The process of pulmonary organogenesis requires the generation of precise signaling centers that are linked to transcriptional programs that, in turn, regulate cell numbers, differentiation, and behavior, as branching morphogenesis and alveolarization proceed. This review summarizes knowledge regarding the expression and proposed roles of transcription factors influencing lung formation and function with particular focus on knowledge derived from the study of the mouse. A group of transcription factors active in the endodermally derived cells of the developing lung tubules, including thyroid transcription factor-1 (TTF-1), beta-catenin, Forkhead orthologs (FOX), GATA, SOX, and ETS family members are required for normal lung morphogenesis and function. In contrast, a group of distinct proteins, including FOXF1, POD1, GLI, and HOX family members, play important roles in the developing lung mesenchyme, from which pulmonary vessels and bronchial smooth muscle develop. Lung formation is dependent on reciprocal signaling among cells of both endodermal and mesenchymal compartments that instruct transcriptional processes mediating lung formation and adaptation to breathing after birth.
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            Computational and experimental identification of novel human imprinted genes.

            Imprinted genes are essential in embryonic development, and imprinting dysregulation contributes to human disease. We report two new human imprinted genes: KCNK9 is predominantly expressed in the brain, is a known oncogene, and may be involved in bipolar disorder and epilepsy, while DLGAP2 is a candidate bladder cancer tumor suppressor. Both genes lie on chromosome 8, not previously suspected to contain imprinted genes. We identified these genes, along with 154 others, based on the predictions of multiple classification algorithms using DNA sequence characteristics as features. Our findings demonstrate that DNA sequence characteristics, including recombination hot spots, are sufficient to accurately predict the imprinting status of individual genes in the human genome.
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              Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation.

              We observed two unrelated consanguineous families with malformation syndromes sharing anophthalmia and distinct eyebrows as common signs, but differing for alveolar capillary dysplasia or complex congenital heart defect in one and diaphragmatic hernia in the other family. Homozygosity mapping revealed linkage to a common locus on chromosome 15, and pathogenic homozygous mutations were identified in STRA6, a member of a large group of "stimulated by retinoic acid" genes encoding novel transmembrane proteins, transcription factors, and secreted signaling molecules or proteins of largely unknown function. Subsequently, homozygous STRA6 mutations were also demonstrated in 3 of 13 patients chosen on the basis of significant phenotypic overlap to the original cases. While a homozygous deletion generating a premature stop codon (p.G50AfsX22) led to absence of the immunoreactive protein in patient's fibroblast culture, structural analysis of three missense mutations (P90L, P293L, and T321P) suggested significant effects on the geometry of the loops connecting the transmembrane helices of STRA6. Two further variations in the C-terminus (T644M and R655C) alter specific functional sites, an SH2-binding motif and a phosphorylation site, respectively. STRA6 mutations thus define a pleiotropic malformation syndrome representing the first human phenotype associated with mutations in a gene from the "STRA" group.
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                Author and article information

                Journal
                Am J Hum Genet
                American Journal of Human Genetics
                Elsevier
                0002-9297
                1537-6605
                12 June 2009
                : 84
                : 6
                : 780-791
                Affiliations
                1Dept of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
                2Dept of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
                3Dept of Pediatrics – Nutrition, Baylor College of Medicine, Houston, TX 77030, USA
                4Institute of Child Health, WC1N 1EH London, UK
                5Wellcome Trust Sanger Institute, Hinxton, CB10 1SA Cambridge, UK
                6Signature Genomic Laboratories, LLC, Spokane, WA 99207, USA
                7Division of Pediatric Genetics and Metabolism, University of Florida College of Medicine, Gainesville, FL 32610, USA
                8Dept of Cardiology, Miami Children's Hospital, Miami, FL 33155, USA
                9Dept of Genetics, Miami Children's Hospital, Miami, FL 33155, USA
                10Division of Human Genetics, Children's Hospital of Philadelphia, PA 19104, USA
                11Dept of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 3K9, Canada
                12Dept of Medical Genetics, University of Washington, Seattle, WA 98195, USA
                13Dept of Medical Genetics, Addenbrooke's Hospital, CB2 0QQ Cambridge, UK
                14Dept of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA
                Author notes
                []Corresponding author pawels@ 123456bcm.edu
                [15]

                These authors contributed equally to this work

                Article
                AJHG404
                10.1016/j.ajhg.2009.05.005
                2694971
                19500772
                © 2009 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved..

                This document may be redistributed and reused, subject to certain conditions.

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                Genetics

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