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Title: NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects
Authors: Lu, Weining ×
Quintero-Rivera, Fabiola
Fan, Yanli
Alkuraya, Fowzan S
Donovan, Diana J
Xi, Qiongchao
Turbe-Doan, Annick
Li, Qing-Gang
Campbell, Craig G
Shanske, Alan L
Sherr, Elliott H
Ahmad, Ayesha
Peters, Roxana
Rilliet, Benedict
Parvex, Paloma
Bassuk, Alexander G
Harris, David J
Ferguson, Heather
Kelly, Chantal
Walsh, Christopher A
Gronostajski, Richard M
Devriendt, Koenraad
Higgins, Anne
Ligon, Azra H
Quade, Bradley J
Morton, Cynthia C
Gusella, James F
Maas, Richard L #
Issue Date: May-2007
Publisher: Public Library of Science
Series Title: PLoS Genetics vol:3 issue:5 pages:830-843
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.
URI: 
ISSN: 1553-7390
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical Genetics
Clinical Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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