THE HUMAN PLAKOGLOBIN GENE LOCALIZES ON CHROMOSOME 17Q21 AND IS SUBJECTED TO LOSS OF HETEROZYGOSITY IN BREAST AND OVARIAN CANCERS
THE HUMAN PLAKOGLOBIN GENE LOCALIZES ON CHROMOSOME 17Q21 AND IS SUBJECTED TO LOSS OF HETEROZYGOSITY IN BREAST AND OVARIAN CANCERS
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DOI：
10.1073/pnas.92.14.6384
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发表时间：
1995-07-03
影响因子：
11.1
通讯作者：
KEMLER, R
中科院分区：
文献类型：
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作者：
ABERLE, H;BIERKAMP, C;KEMLER, R
编码人斑珠蛋白的基因被定位到染色体 17q12-q22。使用基因内限制性片段长度多态性将斑珠蛋白基因定位于基因座 KRT10 的远端和标记 D17S858 的近端。 plakoglobin 基因与多态性 17q21 标记 UM8 共定位于同一粘粒插入片段上。已知 17 号染色体的这个亚区域在散发性乳腺和卵巢肿瘤中特别容易受到遗传改变的影响。我们发现乳腺和卵巢肿瘤中斑珠蛋白基因杂合性丧失。我们已经鉴定了斑珠蛋白编码序列中的低频多态性，其导致蛋白质的氨基酸位置142处的精氨酸被组氨酸取代，以及编码序列的核苷酸位置332处的沉默突变。这种多态性使我们能够证明斑珠蛋白与家族性乳腺癌和卵巢癌易感性之间的等位基因关联。我们的结果，加上目前关于斑珠蛋白生物学功能的知识，表明斑珠蛋白可能代表乳腺癌和卵巢癌的假定肿瘤抑制基因。
The gene encoding human plakoglobin was mapped to chromosome 17q12-q22. An intragenic restriction fragment length polymorphism was used to localize the plakoglobin gene distal to locus KRT10 and proximal to the marker D17S858. The plakoglobin gene colocalizes with the polymorphic 17q21 marker UM8 on the same cosmid insert. This subregion of chromosome 17 is known to be particularly subjected to genetic alterations in sporadic breast and ovarian tumors. We show loss of heterozygosity of the plakoglobin gene in breast and ovarian tumors. We have identified a low-frequency polymorphism in the plakoglobin coding sequence which results in an arginine to histidine substitution at amino acid position 142 of the protein, as well as a silent mutation at nucleotide position 332 of the coding sequence. This polymorphism allowed us to demonstrate an allelic association of plakoglobin with predisposition to familial breast and ovarian cancers. Our results, together with the present knowledge about the biological function of plakoglobin, suggest that plakoglobin might represent a putative tumor suppressor gene for breast and ovarian cancers.