MODY-like diabetes associated with an apparently balanced translocation: possible involvement of MPP7 gene and cell polarity in the pathogenesis of diabetes

Abstract

Background: Characterization of disease-associated balanced translocations has led to the discovery of genes responsible for many disorders, including syndromes that include various forms of diabetes mellitus. We studied a man with unexplained maturity onset diabetes of the young (MODY)-like diabetes and an apparently balanced translocation [46,XY,t(7;10)(q22;p12)] and sought to identify a novel diabetes locus by characterizing the translocation breakpoints.

Results: Mutations in coding exons and splice sites of known MODY genes were first ruled out by PCR amplification and DNA sequencing. Fluorescent in situ hybridization (FISH) studies demonstrated that the translocation did not disrupt two known diabetes-related genes on 10p12. The translocation breakpoints were further mapped to high resolution using FISH and somatic cell hybrids and the junctions PCR-amplified and sequenced. The translocation did not disrupt any annotated transcription unit. However, the chromosome 10 breakpoint was 220 kilobases 5' to the Membrane Protein, Palmitoylated 7 (MPP7) gene, which encodes a protein required for proper cell polarity. This biological function is shared by HNF4A, a known MODY gene. Databases show MPP7 is highly expressed in mouse pancreas and is expressed in human islets. The translocation did not appear to alter lymphoblastoid expression of MPP7 or other genes near the breakpoints.

Conclusion: The balanced translocation and MODY-like diabetes in the proband could be coincidental. Alternatively, the translocation may cause islet cell dysfunction by altering MPP7 expression in a subtle or tissue-specific fashion. The potential roles of MPP7 mutations in diabetes and perturbed islet cell polarity in insulin secretion warrant further study.

Figure 1

A. Pedigree of proband with MODY-like diabetes and a balanced 7;10 translocation. B. Partial G-banded karyotype of proband showing normal and derivative chromosomes 7 and 10. Arrows indicate breakpoints.

Figure 2

A. Sequences of PCR products from junctions aligned to reference human genome sequence. Upper case, chromosome 10 sequences. Lower case, chromosome 7 sequences. Upper case italics, origin unknown. B. UCSC Genome Browser tracks showing genes flanking the translocation breakpoints (arrows) and BAC clones used for FISH. C. FISH showing three signals for chromosome 7 (left) and chromosome 10 (right) BAC probes shown in B. D. Cartoon illustrating orientation of flanking genes and relative distances from translocation breakpoints.

Figure 3

Electropherograms showing heterozygous nucleotides (arrows) in RT-PCR products from MPP7, WAC, and MTERF heterogeneous nuclear RNA indicating biallelic transcription.