Carpten J D, Robbins C M, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds W F, Gillanders E M, Kennedy A M, Chen J D, Agarwal S K, Sood R, Jones M P, Moses T Y, Haven C, Petillo D, Leotlela P D, Harding B, Cameron D, Pannett A A, Höög A, Heath H, James-Newton L A, Robinson B, Zarbo R J, Cavaco B M, Wassif W, Perrier N D, Rosen I B, Kristoffersson U, Turnpenny P D, Farnebo L-O, Besser G M, Jackson C E, Morreau H, Trent J M, Thakker R V, Marx S J, Teh B T, Larsson C, Hobbs M R
Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Genet. 2002 Dec;32(4):676-80. doi: 10.1038/ng1048. Epub 2002 Nov 18.
We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.
我们在此报告了一个与甲状旁腺功能亢进-颌骨肿瘤（HPT-JT）综合征相关的基因的鉴定结果。此前，一个与HPT-JT相关的单一位点（HRPT2）被定位到染色体区域1q25-q32。我们通过对26个患病家族进行基因分型，将该区域缩小至一个12厘摩的关键区间。采用定位候选基因法，我们在14个患有HPT-JT的家族中，于一个单基因内鉴定出13种不同的杂合、种系失活突变。在48个具有囊性特征的甲状旁腺腺瘤中进行的突变筛查支持了HRPT2作为肿瘤抑制基因的作用，该筛查鉴定出3种体细胞失活突变，均位于外显子1。在正常对照中未检测到这些突变，并且所有这些突变预计都会导致蛋白质功能缺陷或受损。HRPT2是一个广泛表达、进化保守的基因，编码一种预测含有531个氨基酸的蛋白质，我们将其命名为副纤维蛋白。我们的研究结果表明，HRPT2是一个肿瘤抑制基因，其失活直接参与了HPT-JT的易感性以及一些散发性甲状旁腺肿瘤的发生发展。
