Bhoj Elizabeth J, Romeo Stefano, Baroni Marco G, Bartov Guy, Schultz Roger A, Zinn Andrew R
McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Mol Cytogenet. 2009 Feb 13;2:5. doi: 10.1186/1755-8166-2-5.
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.
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.
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.
对疾病相关平衡易位的特征分析已促成了许多负责多种疾病的基因的发现，包括各种形式糖尿病的综合征。我们研究了一名患有不明原因的青年起病成年型糖尿病（MODY）样糖尿病且有明显平衡易位[46,XY,t(7;10)(q22;p12)]的男性，并试图通过对易位断点进行特征分析来确定一个新的糖尿病基因座。
首先通过聚合酶链反应（PCR）扩增和DNA测序排除了已知MODY基因编码外显子和剪接位点的突变。荧光原位杂交（FISH）研究表明，该易位未破坏10p12上两个已知的糖尿病相关基因。使用FISH和体细胞杂种将易位断点进一步定位到高分辨率，并对连接点进行PCR扩增和测序。该易位未破坏任何注释的转录单元。然而，10号染色体断点位于膜蛋白棕榈酰化7（MPP7）基因5'端220千碱基处，该基因编码细胞极性正常所需的一种蛋白质。这种生物学功能由已知的MODY基因肝细胞核因子4α（HNF4A）共享。数据库显示MPP7在小鼠胰腺中高度表达，且在人胰岛中表达。该易位似乎未改变MPP7或断点附近其他基因的淋巴母细胞表达。
先证者中的平衡易位与MODY样糖尿病可能是巧合。或者，该易位可能通过以微妙或组织特异性方式改变MPP7表达而导致胰岛细胞功能障碍。MPP7突变在糖尿病中的潜在作用以及胰岛素分泌中胰岛细胞极性紊乱值得进一步研究。
