Using Balanced Translocation to Discover Novel Disease Causing Genes: Potential Involvement of Basonuclin 2 in Congenital Heart Disease and Palmitoylated Membrane Protein 7 in Maturity-Onset Diabetes of the Young
Bhoj, Elizabeth Joyce
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Patients with balanced chromosomal translocations and disease have been used to identify novel disease-causing genes by examining the genes affected by the chromosomal breakpoints. We have identified a man with unexplained maturity-onset diabetes of the young (MODY) and a balanced translocation (7q22;10p12), and a man carrying a balanced translocation associated with partial anomalous pulmonary venous return (PAPVR) and hypospadias. / In our first proband, the translocation breakpoints were mapped to high resolution using FISH and somatic cell hybrids and the junctions amplified by PCR and sequenced. No annotated genes were disrupted by the translocation. Three of the four genes bordering the translocation breakpoints showed biallelic transcription in lymphoblastoid cells; the other gene did not have any informative SNPs. The 10p12 breakpoint was 220 kb 5’ to the Membrane Protein, Palmitoylated (MPP7) gene, which encodes a protein required for proper cell polarity. As this biological function is shared by HNF4A, a known MODY gene, the translocation may cause islet cell dysfunction by altering MPP7 expression in a tissue- or a cell-specific fashion. / In our second proband, tiling array comparative genomic hybridization (aCGH) for chromosomes 9 and 13 was performed on DNA from cultured cells from the productions of conception of his offspring with karyotype (46,XX,der(9)t(9;13)(p22;q22). The results mapped both breakpoints to kilobase resolution. The chromosome 13 breakpoint lies in an intergenic region. The nearest gene, Lim-domain Only 7 (LMO7), is ~400 kb away. The chromosome 9 breakpoint lies within an intron of basonuclin 2 (BNC2), a gene of unknown function with a complex pattern of alternative transcripts. Expression of LMO7 and BNC2 is enriched in fetal heart and penis. Transcripts from both alleles of LMO7 and BNC2 were present in immortalized lymphocytes with the balanced translocation. One BNC2 missense mutation of unclear significance was identified among 10 patients with sporadic total or PAPVR.