Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development

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 B400 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 À/À 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.

The zinc-finger protein basonuclin 2 is required for proper mitotic arrest, prevention of premature meiotic initiation and meiotic progression in mouse male germ cells

“…Nonsteroidogenic interstitial cells include macrophages, myoid cells and mesenchymal cells (Skinner, 1991). Because BNC2 has been found in several kinds of mesenchymal cells, it is possible that BNC2 also resides in mesenchymal cells in the testis, where it might have a function in cell multiplication, as it does in the developing palate and urethra (Bhoj et al, 2011;Vanhoutteghem et al, 2009). …”

The Drosophila genesdisconnectedanddisco-relatedtogether specify development of adult legs

“…Indeed, our earlier work established that the single Tribolium homologue, Tc-disco, specified portions of the legs and other ventral appendages in this beetle (Patel et al, 2007). Further support for a conserved role comes from a report uncovering a possible link between a break in one of the human disco homologs, Basonuclin-2, and limb growth in humans (Bhoj et al, 2011). If this is indeed a causative mutation, then it is possible that the appendage role of the disco genes is conserved.…”

Basonuclines et protéines DISCO

“…Il est possible que la létalité de la mutation masque d'autres phénotypes, affectant par exemple les cellules germinales mâles et femelles dans lesquelles BNC2 est très abondante (non publié). Une greffe des gonades bnc2 -/-chez des souris immunodéficitaires [7] à des anomalies de la croissance osseuse a été décrit récemment [16]. La symptomatologie résulte d'une translocation dont le point de cassure, situé dans le gène BNC2, entraîne la synthèse d'une protéine sans doigts de zinc, donc non fonctionnelle.…”