MOLECULAR ANALYSIS OF THE NEVOID BASAL CELL CARCINOMA GENE

痣样基底细胞癌综合征（NBCCS）是一种常染色体 以多发性基底细胞癌为特征的显性疾病 （基底细胞癌），手掌和脚底的凹陷，颌骨的角化囊肿，以及 各种其他肿瘤和发育异常。 NBCCS是 定位于染色体9q22.3;家族性和散发性BCC 显示该区域标记的杂合性缺失，与 该基因是肿瘤抑制基因。 人序列（PTC）， 与果蝇体节极性基因patched有很强的同源性， 分离自NBCCS区域的YAC和粘粒重叠群，并显示 在NBCCS患者的许多受影响的组织中表达。 亲水性分析表明，人类补丁是一个完整的膜 疏水和亲水伸展模式相似的蛋白质 与果蝇的相似 在发育中的小鼠胚胎中， 最初在腹侧神经管中检测到， 体节和肢芽。 在肢芽中的表达仅限于 围绕极化活动区的后外胚层。 的 结果表明，修补是在一个互补的模式， Sonic hedgehog是果蝇hedgehog的一种小鼠同源物， 补丁/刺猬的相互作用在 进化 单链构象多态性分析和 测序揭示了患有该综合征的患者中的PTC突变， 相关的肿瘤。 我们建议，减少表达的 补丁基因可以导致发育异常， 该综合征和补丁功能完全丧失有助于 某些细胞类型的转化。

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, keratocysts of the jaw, and a variety of other tumors and developmental abnormalities. NBCCS was mapped to chromosome 9q22.3; and both familial and sporadic BCCs display loss of heterozygosity for markers in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region and shown to be expressed in many of the tissues affected in NBCCS patients. Hydropathy analysis suggests that human patched is an integral membrane protein with a pattern of hydrophobic and hydrophilic stretches similar to that of Drosophila patched. In the developing mouse embryo, patched is initially detected within the ventral neural tube and later in the somites and limb buds. Expression in the limb buds is restricted to posterior ectoderm surrounding the zone of polarizing activity. The results show that patched is expressed in a complementary pattern to Sonic hedgehog, a murine homologue of Drosophila hedgehog and suggest that patched/hedgehog interactions have been conserved during evolution. Single-stranded conformation polymorphism analysis and sequencing revealed mutations of PTC in patients with the syndrome and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.