Journal article
NFIA Haploinsufficiency Is Associated with a CNS Malformation Syndrome and Urinary Tract Defects
PLoS genetics, Vol.3(5), pp.830-843
05/2007
DOI: 10.1371/journal.pgen.0030080
PMCID: PMC1877820
PMID: 17530927
Abstract
Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia(-/-) knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia(+/-) and Nfia(-/-) phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia(+/-) and Nfia(-/-) mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects.
Details
- Title: Subtitle
- NFIA Haploinsufficiency Is Associated with a CNS Malformation Syndrome and Urinary Tract Defects
- Creators
- Weining Lu - Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaFabiola Quintero-Rivera - Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaYanli Fan - Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaFowzan S Alkuraya - Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaDiana J Donovan - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaQiongchao Xi - Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaAnnick Turbe-Doan - Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaQing-Gang Li - Renal Section, Boston University Medical Center, Boston, Massachusetts, United States of AmericaCraig G Campbell - Division of Neurology, Children's Hospital of Western Ontario, London, Ontario, CanadaAlan L Shanske - Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, United States of AmericaElliott H Sherr - Department of Neurology, University of California San Francisco, San Francisco, California, United States of AmericaAyesha Ahmad - Division of Genetic and Metabolic Disorders, Department of Pediatrics, Wayne State University, Detroit, Michigan, United States of AmericaRoxana Peters - Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaBenedict Rilliet - Department of Neurosurgery, University Hospital, Geneva, SwitzerlandPaloma Parvex - Department of Nephrology, University Hospital, Geneva, SwitzerlandAlexander G Bassuk - Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of AmericaDavid J Harris - Genetics Division, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, United States of AmericaHeather Ferguson - Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaChantal Kelly - Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaChristopher A Walsh - Genetics Division, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, United States of AmericaRichard M Gronostajski - Department of Biochemistry, State University of New York at Buffalo, Buffalo, New York, United States of AmericaKoenraad Devriendt - Centre for Human Genetics, University of Leuven, Leuven, BelgiumAnne Higgins - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaAzra H Ligon - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaBradley J Quade - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaCynthia C Morton - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaJames F Gusella - Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of AmericaRichard L Maas - Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.3(5), pp.830-843
- DOI
- 10.1371/journal.pgen.0030080
- PMID
- 17530927
- PMCID
- PMC1877820
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library of Science; San Francisco, USA
- Alternative title
- NFIA Haploinsufficiency in Human and Mouse
- Language
- English
- Date published
- 05/2007
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984020617802771
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