TY - JOUR
T1 - Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development
AU - Bhoj, Elizabeth J.
AU - Ramos, Purita
AU - Baker, Linda A.
AU - Cost, Nicholas
AU - Nordenskjöld, Agneta
AU - Elder, Frederick F.
AU - Bleyl, Steven B.
AU - Bowles, Neil E.
AU - Arrington, Cammon B.
AU - Delhomme, Brigitte
AU - Vanhoutteghem, Amandine
AU - Djian, Philippe
AU - Zinn, Andrew R.
N1 - Funding Information:
Human studies were funded by a UT Southwestern High Risk/High Impact grant (ARZ), NIH R01 DK59164 (LAB), and Children’s Medical Center at Dallas CCRAC Grant #2006-92 (LAB). Mouse studies were funded by the Association pour la Recherche sur le Cancer and the Ligue contre le Cancer (PD).
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
KW - Basonuclin 2
KW - Birth defects
KW - Hypospadias
KW - Urethra
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U2 - 10.1038/ejhg.2010.245
DO - 10.1038/ejhg.2010.245
M3 - Article
C2 - 21368915
AN - SCOPUS:79955773544
SN - 1018-4813
VL - 19
SP - 540
EP - 546
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 5
ER -