Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.
Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.
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DOI：
10.1186/s40478-016-0328-1
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发表时间：
2016-06-01
影响因子：
7.1
通讯作者：
Korbonits M
中科院分区：
文献类型：
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作者：
Iacovazzo D;Caswell R;Bunce B;Jose S;Yuan B;Hernández-Ramírez LC;Kapur S;Caimari F;Evanson J;Ferraù F;Dang MN;Gabrovska P;Larkin SJ;Ansorge O;Rodd C;Vance ML;Ramírez-Renteria C;Mercado M;Goldstone AP;Buchfelder M;Burren CP;Gurlek A;Dutta P;Choong CS;Cheetham T;Trivellin G;Stratakis CA;Lopes MB;Grossman AB;Trouillas J;Lupski JR;Ellard S;Sampson JR;Roncaroli F;Korbonits M
非综合征性垂体巨人症可能是由AIP突变或最近发现的导致X连锁肢端巨人症(XLAG)的Xq26.3微重复引起的。在Xq26.3中，GPR101被认为是致病基因，这个孤儿G蛋白偶联受体中的c.924G >； C(p.E308D)变异被认为在肢端肥大症的发病机制中发挥了作用。我们研究了153例垂体巨大症患者(女性58例，男性95例)。对AIP基因突变阴性的病例，采用拷贝数变异、液滴数字聚合酶链式反应和高密度aCGH方法筛查GPR101重复序列。对XLAG患者的遗传、临床和组织病理学特征进行了详细研究。对395例肢端肥大症患者外周血和193例垂体瘤DNA样本进行了GPR101变异检测。我们确定了12名XLAG患者(10名女性和2名男性；7.8%)。在一个受试者中，重复区域只包含GPR101，但在先前报道的患者中发现其他三个基因是重复的，定义了一个新的最小的重复重叠区域。当女性患者出现生殖系突变时，两名男性患者携带的突变处于嵌合体状态。9例为垂体腺瘤，3例为腺体增生症。比较XLAG、AIP阳性和GPR101及AIP阴性患者在性别分布、发病年龄、身高、催乳素分泌和组织学特征方面的差异。XLAG相关腺瘤的病理特征非常相似。这些肿瘤呈窦状和小叶状结构。稀疏和密集颗粒的生长激素细胞与乳酸菌混合，常可见滤泡样结构和钙化。与公共数据库相比，散发的家族性肢端肥大症患者没有增加C.924G >； C(p.E308D)GPR101变异的患病率。综上所述，XLAG可能源于GPR101的生殖系或体细胞复制。仅GPR101的复制就足以导致XLAG的发生，这意味着它是Xq26.3区域内的致病基因。XLAG相关的垂体腺瘤的病理特征是典型的，结合临床表型，应该促使进行基因检测。本文的在线版本(doi：10.1186/s40478-0160328-1)包含补充材料，授权用户可以使用。
Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly. We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants. We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases. In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing. The online version of this article (doi:10.1186/s40478-016-0328-1) contains supplementary material, which is available to authorized users.