Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome.
Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome.
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DOI：
10.1210/jc.2017-00332
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发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Levine MA
中科院分区：
文献类型：
--
作者：
McCormack SE;Li D;Kim YJ;Lee JY;Kim SH;Rapaport R;Levine MA
垂体柄中断综合征（PSIS，ORPHA 95496）是一种先天性垂体缺陷，其特征为垂体柄非常细/中断、垂体后叶异位（或缺失）和垂体前叶发育不全或发育不全三联征。这种疾病的复杂遗传模式越来越多地被认识到。本研究的目的是确定一个受影响的儿童PSIS的遗传原因。通过使用标准技术进行全外显子组测序（WES），通过桑格测序确认优先的遗传变体。为了研究一种候选变体对突变体WDR 11功能的影响，使用Western印迹和共免疫荧光来评估结合能力，并使用沿着免疫荧光的来评估核定位的链霉素B暴露。我们描述了一个儿童谁提出在婴儿期合并垂体激素缺乏症，其脑成像显示一个小垂体前叶，异位垂体后叶，和一个薄，中断柄。WES证明了垂体发育所需的两个基因中的杂合错义突变，一个是从未受影响的母亲遗传的PROKR 2（c.253C>T;p.R85C）中的已知功能丧失突变，另一个是从未受影响的父亲遗传的WDR 11（c.1306A>G;p.I436V）突变。突变体WDR 11失去了与其功能伴侣EMX 1结合并定位于细胞核的能力。一个PSIS患儿及其未受影响的家庭的WES暗示了一种双基因遗传机制。在垂体功能减退症的情况下，其中有一个单基因型与表型的不完全分离，第二个遗传位点参与的可能性应予以考虑。一个遗传原因是在一个孩子与组合多种垂体激素缺乏症。这些发现暗示了一种双基因遗传机制，在PROKR 2和WDR 11中存在突变。
Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland characterized by the triad of a very thin/interrupted pituitary stalk, an ectopic (or absent) posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland. Complex genetic patterns of inheritance of this disorder are increasingly recognized. The objective of this study was to identify a genetic cause of PSIS in an affected child. Whole exome sequencing (WES) was performed by using standard techniques, with prioritized genetic variants confirmed via Sanger sequencing. To investigate the effects of one candidate variant on mutant WDR11 function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization. We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus. WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered. A genetic cause was sought in a child with combined multiple pituitary hormone deficiencies. The findings implicate a digenic mechanism of inheritance, with a mutation in PROKR2 and in WDR11.
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DOI：
10.1073/pnas.0707173104
发表时间：
2007-10-30
影响因子：
11.1
作者：
Pitteloud, Nelly;Zhang, Chengkang;Crowley, William F., Jr.
通讯作者：
Crowley, William F., Jr.
影响因子：
3.5
作者：
Monnier, Carine;Dode, Catherine;Rondard, Philippe
通讯作者：
Rondard, Philippe
影响因子：
2.9
作者：
Correa FA;Trarbach EB;Tusset C;Latronico AC;Montenegro LR;Carvalho LR;Franca MM;Otto AP;Costalonga EF;Brito VN;Abreu AP;Nishi MY;Jorge AA;Arnhold IJ;Sidis Y;Pitteloud N;Mendonca BB
通讯作者：
Mendonca BB
影响因子：
5.8
作者：
Choi, Yongwook;Chan, Agnes P.
通讯作者：
Chan, Agnes P.
影响因子：
4
作者：
Schäffer AA
通讯作者：
Schäffer AA