Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.
Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.
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DOI：
10.1056/nejmoa1408028
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发表时间：
2014-12-18
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影响因子：
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通讯作者：
Stratakis CA
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作者：
Trivellin G;Daly AF;Faucz FR;Yuan B;Rostomyan L;Larco DO;Schernthaner-Reiter MH;Szarek E;Leal LF;Caberg JH;Castermans E;Villa C;Dimopoulos A;Chittiboina P;Xekouki P;Shah N;Metzger D;Lysy PA;Ferrante E;Strebkova N;Mazerkina N;Zatelli MC;Lodish M;Horvath A;de Alexandre RB;Manning AD;Levy I;Keil MF;Sierra Mde L;Palmeira L;Coppieters W;Georges M;Naves LA;Jamar M;Bours V;Wu TJ;Choong CS;Bertherat J;Chanson P;Kamenický P;Farrell WE;Barlier A;Quezado M;Bjelobaba I;Stojilkovic SS;Wess J;Costanzi S;Liu P;Lupski JR;Beckers A;Stratakis CA
生长激素分泌增加导致儿童肥胖症和成人肢端肥大症;肥胖症和肢端肥大症的遗传原因知之甚少。我们对43例肢端肥大症患者的样本进行了临床和遗传学研究，然后对248例肢端肥大症患者样本中的相关基因进行了测序。我们观察到染色体Xq26.3的微重复在13例患者的样本中，这些样本中，4个是从两个无关的kinetics的成员，9个是从散发病例的患者。所有患者均在儿童早期发病。在没有携带Xq26.3微重复的自闭症患者中，没有人在5岁之前出现。Xq26.3区域的基因组特征表明，微重复是在染色体复制过程中产生的，它们含有四个蛋白质编码基因。其中只有一个基因，即编码G蛋白偶联受体的GPR 101，在患者的垂体病变中过表达。我们在248例肢端肥大症患者中的11例中发现了复发性GPR 101突变（p.E308D），该突变主要见于肿瘤。当该突变被转染到大鼠GH 3细胞中时，它导致生长激素的释放增加和生长激素产生细胞的增殖。我们描述了一种由Xq26.3基因组重复引起的儿科疾病（我们称之为X连锁肢端肥大症[X-LAG]），其特征是生长激素过量引起的早发性肢端肥大症。GPR 101的重复可能导致X-LAG。我们还发现了一个复发性突变GPR 101在一些成人肢端肥大症。（由Eunice Kennedy Shriver国家儿童健康和人类发展研究所和其他机构资助。
Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients’ pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells. We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)