NFIA Haploinsufficiency Is Associated with a CNS Malformation Syndrome and Urinary Tract Defects

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.

Alterations of NFIA in chronic malignant myeloid diseases

“…2,3 Mechanistically, Bortezomib binds the active sites of the enzymes in the b-subunits located in the proteolytic chamber of the 20S proteasome. 4 Molecules that inhibit the proteasome through a different mechanism would be useful probes to understand the activity of this enzyme complex and potentially new therapeutic agents.…”

“…1 The NFI proteins comprise a DNA binding and dimerization domain in their N-terminal half, which contains four cysteine residues common to the four vertebrate members and conserved in the nonvertebrate orthologs, and a transactivation and repression domain in their C-terminal half (Figure 1a). The NFIA gene, located in the 1p31 chromosomal region, has a function in brain, [2][3][4] ureteral and renal development 3 as well as hematopoiesis. 5,6 Interactions of NFIA with CEBPa and PU.1 through microRNAs regulate granulocytic and monocytic differentiation, respectively.…”

“…However, NFIA haplo-insufficiency has a deleterious effect when occurring in germinal cells in the mouse. 3 Increased expression of NFIB mRNA in granulocytes has been described in PV, 13 which may suggest a compensatory or antagonist function of NFIB.…”

CANPMR Syndrome and Chromosome 1p32-p31 Deletion Syndrome Coexist in Two Related Individuals Affected by Simultaneous Haplo-insufficiency of CAMTA1 and NIFA Genes

“…Some years later, Lu et al proposed the causal association between this malformation syndrome and Nuclear Factor 1 A (NFIA) haplo-insufficiency [17]. NFIA maps on 1p31.2, carries 11 exons and produces at least 9 different protein isoforms [18][19][20].…”

Long Noncoding RNA–MicroRNA Pathway Controlling Nuclear Factor IA , A Novel Atherosclerosis Modifier Gene

“…The latter might be related to the more severe phenotype seen in patients with NFIA deletions and in knockout mice, both showing malformations of the central nervous system. 7,8 It therefore seems that NFIA has a large number of functions, which is plausible for its role as a transcription factor.…”