Tsou H C, Ping X L, Xie X X, Gruener A C, Zhang H, Nini R, Swisshelm K, Sybert V, Diamond T M, Sutphen R, Peacocke M
Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Hum Genet. 1998 Apr;102(4):467-73. doi: 10.1007/s004390050723.
Cowden's syndrome (CS) is an autosomal dominant disorder associated with an increased risk of developing benign and malignant tumors in a variety of tissues, including the skin, thyroid, breast and brain. Women with CS are felt to have an increased risk of developing breast cancer, and virtually all women with CS develop bilateral fibrocystic disease of the breast. Recently, a series of germline mutations have been identified from CS families in a gene known as PTEN/MMAC1/TEP1. In this study, we used heteroduplex analysis and direct sequencing analysis and identified three novel germline mutations in the PTEN/MMAC1/TEP1 coding sequence from unrelated individuals with CS. We report a de novo transition (T-->C) at nucleotide 335 in exon 5. This missense mutation resulted in a leucine to proline (CTA to CCA) change at codon 112. We also describe a novel splice site mutation (801+2T-->G) in intron 7 that caused exon skipping in PTEN/MMAC1/TEP1 mRNA. The third mutation we report is a missense mutation, consisting of a transition (T-->C) at nucleotide 202 in exon 3, resulting in a tyrosine to histidine (TAC to CAC) change at codon 68. Finally, we also detected a rare polymorphism in exon 7 of the PTEN/MMAC1/TEP1 coding sequence. These data confirm the observation that mutations of the PTEN/MMAC1/TEP1 coding sequence are responsible for at least some cases of CS, and further define the spectrum of mutations in this autosomal dominant disorder.
考登综合征（CS）是一种常染色体显性疾病，与多种组织（包括皮肤、甲状腺、乳腺和脑）发生良性和恶性肿瘤的风险增加相关。患有CS的女性被认为患乳腺癌的风险增加，并且几乎所有患有CS的女性都会发生双侧乳腺纤维囊性疾病。最近，在一个名为PTEN/MMAC1/TEP1的基因中，从CS家族中鉴定出一系列种系突变。在本研究中，我们使用异源双链分析和直接测序分析，从无关的CS个体中鉴定出PTEN/MMAC1/TEP1编码序列中的三个新的种系突变。我们报告了外显子5中第335位核苷酸处的一个新生转换（T→C）。这个错义突变导致密码子112处的亮氨酸变为脯氨酸（CTA变为CCA）。我们还描述了内含子7中的一个新的剪接位点突变（801+2T→G），该突变导致PTEN/MMAC1/TEP1 mRNA中的外显子跳跃。我们报告的第三个突变是一个错义突变，由外显子3中第202位核苷酸处的转换（T→C）组成，导致密码子68处的酪氨酸变为组氨酸（TAC变为CAC）。最后，我们还在PTEN/MMAC1/TEP1编码序列的外显子7中检测到一个罕见的多态性。这些数据证实了PTEN/MMAC1/TEP1编码序列的突变至少在某些CS病例中起作用的观察结果，并进一步确定了这种常染色体显性疾病的突变谱。
