Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Filters applied. Clear all
. 2011 May;19(5):540-6.
doi: 10.1038/ejhg.2010.245. Epub 2011 Feb 2.

Human Balanced Translocation and Mouse Gene Inactivation Implicate Basonuclin 2 in Distal Urethral Development

Affiliations
Free PMC article

Human Balanced Translocation and Mouse Gene Inactivation Implicate Basonuclin 2 in Distal Urethral Development

Elizabeth J Bhoj et al. Eur J Hum Genet. .
Free PMC article

Erratum in

  • Eur J Hum Genet. 2012 Feb;20(2):249. Garg, Vidu [added]

Abstract

We studied a man with distal hypospadias, partial anomalous pulmonary venous return, mild limb-length inequality and a balanced translocation involving chromosomes 9 and 13. To gain insight into the etiology of his birth defects, we mapped the translocation breakpoints by high-resolution comparative genomic hybridization (CGH), using chromosome 9- and 13-specific tiling arrays to analyze genetic material from a spontaneously aborted fetus with unbalanced segregation of the translocation. The chromosome 13 breakpoint was ∼400 kb away from the nearest gene, but the chromosome 9 breakpoint fell within an intron of Basonuclin 2 (BNC2), a gene that encodes an evolutionarily conserved nuclear zinc-finger protein. The BNC2/Bnc2 gene is abundantly expressed in developing mouse and human periurethral tissues. In all, 6 of 48 unrelated subjects with distal hypospadias had nine novel nonsynonymous substitutions in BNC2, five of which were computationally predicted to be deleterious. In comparison, two of 23 controls with normal penile urethra morphology, each had a novel nonsynonymous substitution in BNC2, one of which was predicted to be deleterious. Bnc2(-/-) mice of both sexes displayed a high frequency of distal urethral defects; heterozygotes showed similar defects with reduced penetrance. The association of BNC2 disruption with distal urethral defects and the gene's expression pattern indicate that it functions in urethral development.

Figures

Figure 1
Figure 1
Array CGH and FISH mapping of translocation breakpoints for chromosomes 13 (a) and 9 (b). CGH graphs show coordinates from NCBI 36.1 (hg18) genome assembly (X axis); log2 relative hybridization signal intensity versus control (Y axis). Arrows on metaphase spreads point to hybridization signals (red).
Figure 2
Figure 2
(a) RT-PCR and sequencing demonstrating biallelic expression of LMO7 and BNC2 in lymphoblastoid cells from the proband. K=T/G; Y=C/T. (b) LMO7 and BNC2 expression in lymphoblastoid cell lines from proband vs normal male controls.
Figure 3
Figure 3
β-galactosidase staining (blue) of heterozygous mice carrying a lacZ gene integrated in the Bnc2 locus showing abundant expression in periurethral penile tissues. (a) Transverse section of newborn male mouse through lower abdomen. (b) Enlargment of the penis boxed in (a).
Figure 4
Figure 4
Urethral defects in bnc2+/− and bnc2−/− mice. (a) Gross appearance of external genitalia in newborn males and females (ventral view). In both male and female heterozygous newborns, a narrow epithelialized furrow because of incomplete closure of the urethral folds is visible. In the homozygous mutant the furrow is hypospadic, with a wider and deeper groove than the hets and with a pit-like depression at the distal end. (b) Dye injection into the bladders of newborn males reveals defects in the penile urethral meatus of homozygotes.

Similar articles

See all similar articles

Cited by 10 articles

See all "Cited by" articles

Publication types

Feedback