Dimitri P, Habeb A M, Gurbuz F, Millward A, Wallis S, Moussa K, Akcay T, Taha D, Hogue J, Slavotinek A, Wales J K H, Shetty A, Hawkes D, Hattersley A T, Ellard S, De Franco E
Department of Paediatric Endocrinology (P.D.), Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, United Kingdom; Paediatric Department (A.M.H.), Prince Mohamed Bin Abdulaziz Hospital, National Guard Health Authority, Al-Madinah, Riyadh 14214, Kingdom of Saudi Arabia; Ankara Pediatric Hematology Oncology Education and Training Hospital (F.G.), Ankara, Turkey; Diabetes Clinical Research Centre (A.M.), Plymouth Hospitals NHS Trust, Derriford PL6 8DH, United Kingdom; Department of Paediatrics (S.W.), Bradford Teaching Hospitals NHS Foundation Trust, Bradford, West Yorkshire BD9 6RJ, United Kingdom; Paediatric Department (K.M.), Maternity and Children Hospital, Jeddah 23342, Kingdom of Saudi Arabia; Kanuni Sultan Süleyman Education and Research Hospital (T.A.), 34303 Küçükçekmece, Istanbul, Turkey; Division of Pediatric Endocrinology (D.T.), Children's Hospital of Michigan, Wayne State University, Detroit, Michigan 48201; Department of Paediatrics (J.J.), Madigan Army Medical Center, Tacoma, Washington 98431; Institute for Human Genetics (A.S.), University of California, San Francisco, California 94143; Department of Paediatric Endocrinology and Diabetes (J.K.H.W.), Lady Cilento Children's Hospital, South Brisbane, Queensland 4101, Australia; Department of Paediatrics (A.S.), Nevill Hall Hospital, Abergavenny NP7 7EG, Wales, United Kingdom; Department of Paediatrics (D.H.), Royal Gwent Hospital, Newport NP20 2UB Wales, United Kingdom; and Institute of Biomedical and Clinical Science (A.T.H., S.E., E.D.F.), University of Exeter Medical School, EX2 5DW, United Kingdom.
J Clin Endocrinol Metab. 2015 Oct;100(10):E1362-9. doi: 10.1210/jc.2015-1827. Epub 2015 Aug 10.
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.
GLIS3（GLI 相似蛋白 3）是 GLI 相似锌指蛋白家族的成员，编码一种具有 5 个 C2H2 型锌指结构域的核蛋白。该蛋白在胚胎发育早期表达，作为转录抑制因子和激活因子发挥关键作用。人类 GLIS3 突变极为罕见。
本文旨在确定 12 例具有各种 GLIS3 突变患者的表型表现。
通过聚合酶链反应（PCR）扩增和对第 1 至 11 外显子的序列分析来寻找 GLIS3 基因突变。临床信息由转诊的临床医生提供，随后通过发放问卷以获取更多信息。
我们报告了首例 GLIS3 复合杂合突变患者，该患者未出现先天性甲状腺功能减退。所有患者均表现为新生儿糖尿病，胰岛素敏感性各异。患者的甲状腺疾病各不相同。肝脏和肾脏疾病较为常见，肝功能障碍范围从肝炎到肝硬化；囊性发育异常是最常见的肾脏表现。我们描述了 GLIS3 突变患者新出现的特征，包括颅骨缝早闭、食管裂孔疝、房间隔缺损、脾囊肿和后鼻孔闭锁，并进一步证实了伴有感音神经性耳聋和外分泌性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 突变相关的异常谱，并为 GLIS3 在人类生理发育中的作用提供了新见解。我们队列中的患者除 2 例之外均存活，我们描述了首例活到成年的 GLIS3 突变患者，这表明即使是具有严重 GLIS3 表型的患者，预期寿命可能比最初描述的更长。
