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. 2007 May 25;3(5):e80.
doi: 10.1371/journal.pgen.0030080.

NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects

Weining Lu  1 , Fabiola Quintero-Rivera, Yanli Fan, Fowzan S Alkuraya, Diana J Donovan, Qiongchao Xi, Annick Turbe-Doan, Qing-Gang Li, Craig G Campbell, Alan L Shanske, Elliott H Sherr, Ayesha Ahmad, Roxana Peters, Benedict Rilliet, Paloma Parvex, Alexander G Bassuk, David J Harris, Heather Ferguson, Chantal Kelly, Christopher A Walsh, Richard M Gronostajski, Koenraad Devriendt, Anne Higgins, Azra H Ligon, Bradley J Quade, Cynthia C Morton, James F Gusella, Richard L Maas
Affiliations

NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects

Weining Lu et al. PLoS Genet. .

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.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. CNS and Urinary Tract Defects in Five Individuals with 1p31.3 Rearrangements
(A–J) Brain CT or MRI show a thin corpus callosum in DGAP104 (arrow in A), DGAP089 (arrow in C), and DGAP205–1 (arrow in G); and agenesis of the corpus callosum in DGAP174 (asterisk in E) and DGAP205-1s (asterisk in I). Chiari type I malformation, a downward displacement of the tip of the cerebellar tonsils below the foramen magnum, was found in DGAP104 (arrowhead in A), DGAP174 (arrowhead in E), and DGAP205-1s (arrowhead in I). Congenital ventriculomegaly is present in DGAP089 (D), DGAP174 (F), and DGAP205-1s (J), and hydrocephalus was found in DGAP104 (B) and DGAP205–1 (H). An occipital shunt (arrow in B) was placed in DGAP104 to relieve severe hydrocephalus. (K) DGAP104 MRI shows a tethered spinal cord, with the extremity of the conus medullaris (arrow) at the level of the L4 vertebral body. Arrowhead shows a fishhook deformity of the lower sacral and coccygeal vertebrae. (L) VCUG of DGAP104 depicts left vesicoureteral reflux with retrograde tracking of dye through the ureter into the renal pelvis (arrow) and a right diverticulum at the ureterovesical junction (arrowhead). (M) Spine MRI of DGAP205–1 shows a tethered spinal cord with conus lying at the L3/L4 level (arrow). (N) VCUG of DGAP205–1 shows left vesicoureteral reflux (arrow). (O) Spine MRI of DGAP205-1s depicts a tethered spinal cord with conus lying at L5 (arrow).
Figure 2
Figure 2. NFIA is Deleted or Disrupted in All Five Individuals with 1p31.3 Rearrangements
(A and B) Partial karyogram (A) and ideogram (B) of DGAP104 show the chromosome translocation t(1;20)(p31.3;q13.31)dn. (C) FISH analysis of DGAP104; BAC RP4-802A10 (red signals) hybridizes to the normal Chromosome 1 and der(1) and der(20) chromosomes, thus spanning the 1p31.3 breakpoint. (D) FISH analysis of DGAP089 depicts BAC RP5-902P15 (red signals) hybridization to the normal Chromosome 1 and der(1) and der(2) chromosomes, thus spanning the 1p31.3 breakpoint. (E) FISH analysis reveals that BAC RP5-902P15 (overlapping with NFIA, orange color) is deleted from the der(1) in DGAP174. The nondeleted BAC RP11-134C1 (green) is present on both the normal and derivative Chromosome 1. (F) DGAP205 pedigree with NFIA deletion (arrow indicates the DGAP205–1 proband). DGAP205–1 and half-sister DGAP205-1s have an unbalanced interstitial microdeletion, del(1)(p31.3p32.3), while their phenotypically normal mother DGAP205–2 has a balanced chromosome rearrangement due to an insertion of 1p31.3-p32.3 into Chromosome 4, ins(4;1)(q35;p31.3p32.3). del-NFIA, deletion of NFIA; ins-NFIA, insertion of NFIA. (G and H) FISH analyses show that BAC RP5-902P15 (overlapping with NFIA, orange color) is absent from the der(1) in DGAP205–1 (G) and der (1) in the mother DGAP205–2 (H), but present in the der(4) in the latter (H). The nondeleted BAC RP4-654H19 (green) is present on both the normal and derivative Chromosome 1. (I) NFIA exon–intron structure is shown in the upper part with select exons numbered, and the relevant BAC contig below. Locations of the 1p31.3 translocation breakpoints in DGAP104 and DGAP089 are indicated by red dotted vertical lines. The lower part of (I) depicts 1p31.3–1p32.3 genomic regions with the cytogenetic bands on the short arm of Chromosome 1. TEL represents telomeric orientation, and CEN represents centromeric orientation. Known genes in this region are represented by dots and gene names. FISH-verified BAC clones are represented by horizontal bars. The full names of the BAC clones are listed in Materials and Methods. A 2.2-Mb genomic region deleted in DGAP174 and a ~12-Mb genomic region deleted in DGAP205–1 and 205–1s are shown. Deleted BAC clones tested by FISH are designated in red and nondeleted clones in blue. BAC 802A10 overlaps with NFIA and is deleted.
Figure 3
Figure 3. Nfia Spinal Cord Expression and Syringomyelia Phenotype in Nfia −/− Mice
(A and B) Whole mount in situ hybridization shows abundant Nfia expression in the spinal cord (arrow) of E12.5 (A) and E13.5 (B) mouse embryos. The expression maximum (arrow) transits from rostral to caudal as development proceeds. (C and D) Nfia expression is restricted to the floor plate and spinal ganglia at E11.5 (C), and to the ventral spinal cord at E13.5 (D). (E and F) Spinal cord phenotype in Nfia E18.5 embryos. (E) The lumbar spinal cord central canal is nearly obliterated in wild-type embryos, whereas (F) shows persistent dilation of the lumbar spinal cord central canal (syringomyelia, arrow) in E18.5 Nfia −/− mutants.
Figure 4
Figure 4. Nfia Expression in the Developing Mouse Urinary Tract
(A–D) Whole mount in situ hybridization shows Nfia expression in the developing nephric duct (arrow in A), ureter (arrow in B), and metanephros between E9.5 (not shown) and E16.5, becoming downregulated at E17.5. Reticular pattern of Nfia expression is in the kidney from E14.5–16.5 (C). (E–H) Section in situ hybridizations shows Nfia expression in the ureteral epithelium (arrow in F) and surrounding mesenchyme (arrowhead in F) at E11.5 (F is the enlarged view of boxed region in E), and in stromal mesenchyme (arrows in G and H) at E16.5–17.5. (I) RT-PCR of the developing mouse kidney showing that Nfia is abundantly expressed up to E16.5 and begins to be downregulated at E17.5. β-actin is used as RNA loading control. NB, newborn.
Figure 5
Figure 5. Spectrum of Kidney Phenotypes in Nfia −/− Newborn Mice
Whole mounts of dissected urinary tracts from newborn mice of the indicated genotype (A–F). Normal wild-type newborn kidney and renal histology (A and G); (B) rare Nfia +/− showing hydronephrosis (arrow); (C–F and H–K) Nfia −/− mutants showing bilateral renal agenesis (arrow in C), an elongated, partial duplex kidney with the abnormal cortical zone that demarcates the two poles shown with an arrow (D, H, and I), severely dysplastic kidney with irregular renal surface (arrow in E) and disorganized renal parenchyma (E and J), and nodular Nfia homozygous newborn kidney (F) with renal tubule cystic dilatation (K).
Figure 6
Figure 6. Nfia is Required for Normal Ureteral Development
A Hoxb7-GFP transgenic reporter in the Nfia +/− and Nfia −/− backgrounds reveals ureteral defects in newborn mice. (A–D) Wild-type and Nfia +/− newborns with megaureter (with extent of dilation indicated by two-headed arrow) (A, C) and partial ureteral duplication (arrow) in the mutant (C). Higher power views of boxed areas in (A) and (C), showing distortion of the mutant ureter at the UVJ (B and D); note that the vas deferens in the Nfia +/− male (C) is also GFP–positive. (E and F) Abnormalities in Nfia −/− newborns include proximal flexion of the ureter (E) and dysplastic kidney (F). k, kidney; t, testis; ur, ureter; UVJ, ureterovesical junction; v, vas deferens
Figure 7
Figure 7. Ureter Defects at UPJ and UVJ in Nfia Mutant Mice
(A–C) Hematoxylin and eosin histology depicts duplication and dilatation of ureter at the UPJ in Nfia +/− (B, 60X) and Nfia −/− (C, 60X) newborn mice. (D–F) Hematoxylin and eosin staining shows dilatation of UVJ in some Nfia +/− mutant mice (* in E, 60X); the majority of Nfia +/− and Nfia −/− mice show a normal UVJ (F, 60X). a, abdominal aorta; bl, bladder; pe, pelvis; r, rectum; ur, ureter; UVJ, ureterovesical junction
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