Division of Hematology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
JAMA. 2010 Dec 15;304(23):2611-9. doi: 10.1001/jama.2010.1830.
Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect.
To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro.
DESIGN, SETTING, AND PARTICIPANTS: We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization.
The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein.
We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127.
Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.
嗜铬细胞瘤和副神经节瘤是遗传异质性的神经嵴衍生肿瘤。我们最近在家族性和散发性嗜铬细胞瘤中发现了新型跨膜编码基因 FP/TMEM127 的种系突变，这与肿瘤抑制因子的作用一致。
检测 FP/TMEM127 基因突变在嗜铬细胞瘤和副神经节瘤中的流行率和谱，并检测体外突变的影响。
设计、地点和参与者：我们对 990 名嗜铬细胞瘤和/或副神经节瘤患者的 FP/TMEM127 基因进行了测序，其中包括 898 名来自 8 个独立的全球转诊中心的以前未报告的无其他易感性基因突变的病例，这些病例来自 2009 年 1 月至 2010 年 6 月。开发了一种多重聚合酶链反应（PCR）方法来筛查 545 例这些样本中的大片段基因缺失。共聚焦显微镜观察 5 种转染的突变蛋白，以确定其亚细胞定位。
评估 FP/TMEM127 基因突变或缺失的频率和类型，并与临床变量相关；比较 5 种过表达突变体的亚细胞定位与野生型 FP/TMEM127 蛋白。
我们在 20 个独立的家族中发现了 19 个潜在的致病性 FP/TMEM127 种系突变，但未检测到大片段缺失。所有突变携带者均有肾上腺肿瘤，包括 7 例双侧（P = 2.7×10(-4)) 和/或家族性疾病（20 例样本中的 5 例；P =.005）。FP/TMEM127 突变组的疾病发病年龄中位数与无突变患者相似（分别为 41.5 岁和 45 岁；P =.54）。最常见的表现是 40 岁以上患者的单个良性肾上腺肿瘤。1 名突变携带者发生恶性肿瘤（5%）。在细胞系中表达 5 种新型 FP/TMEM127 突变显示，突变蛋白的弥散定位与野生型 TMEM127 的离散多器官分布不同。
FP/TMEM127 的种系突变与嗜铬细胞瘤有关，但与副神经节瘤无关，且发生在常被排除在遗传筛查算法之外的年龄组。与疾病相关的突变破坏了 FP/TMEM127 蛋白的细胞内分布。
