Expanding the Clinical Spectrum Associated With GLIS3 Mutations.
Expanding the Clinical Spectrum Associated With GLIS3 Mutations.
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DOI：
10.1210/jc.2015-1827
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
De Franco E
中科院分区：
文献类型：
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作者：
Dimitri P;Habeb AM;Gurbuz F;Millward A;Wallis S;Moussa K;Akcay T;Taha D;Hogue J;Slavotinek A;Wales JK;Shetty A;Hawkes D;Hattersley AT;Ellard S;De Franco E
GLIS3 (GLI-similar 3) 是 GLI 类似锌指蛋白家族的成员，编码具有 5 个 C2H2 型锌指结构域的核蛋白。该蛋白在胚胎发生早期表达，作为转录的抑制子和激活子发挥着关键作用。人类 GLIS3 突变极为罕见。本文的目的是确定 12 名具有多种 GLIS3 突变的患者的表型表现。通过 PCR 扩增和外显子 1 至 11 的序列分析来寻找 GLIS3 基因突变。临床信息由转诊临床医生提供，随后使用分发的调查问卷来获取更多信息。我们报告了第一例 GLIS3 复合杂合突变患者，但未出现先天性甲状腺功能减退症。所有患者均患有新生儿糖尿病，并具有一系列胰岛素敏感性。甲状腺疾病因患者而异。肝肾疾病很常见，肝功能障碍从肝炎到肝硬化不等；囊性发育不良是最常见的肾脏表现。我们描述了 GLIS3 突变患者的新表现特征，包括颅缝早闭、食管裂孔疝、房间隔缺损、脾囊肿和后鼻孔闭锁，并证实了更多感音神经性耳聋和外分泌胰腺功能不全的病例。我们报告了 GLIS3 表型的新发现，进一步扩展了与 GLIS3 突变相关的异常范围，并为 GLIS3 在人类生理发育中的作用提供了新的见解。我们的队列中除了 2 名患者外，其余所有患者都还活着，并且我们描述了第一位携带 GLIS3 突变活到成年的患者，这表明即使具有严重 GLIS3 表型的患者的预期寿命也可能比最初描述的更长。
GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare. The purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations. GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information. We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency. We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.