Can Digenic, Tri-Allelic Inheritance of Variants in STAR and CYP11A1 Give Rise to Primary Adrenal Insufficiency? A Case Report.
Can Digenic, Tri-Allelic Inheritance of Variants in STAR and CYP11A1 Give Rise to Primary Adrenal Insufficiency? A Case Report.
复制标题
DOI：
10.3389/fendo.2022.860055
复制
发表时间：
2022
影响因子：
5.2
通讯作者：
Metherell LA
中科院分区：
文献类型：
--
作者：
Ali N;Maharaj AV;Buonocore F;Achermann JC;Metherell LA
1例8岁南亚男孩出现进行性色素沉着，确诊为单纯糖皮质激素缺乏的原发性肾上腺皮质功能不全(PAI)。对这名男孩进行了9年的随访，直到17岁，显示出正常的青春期开始和进展。通过对与PAI相关的候选基因进行定向下一代测序进行的分子评估发现，在类固醇生物合成的早期阶段，有两个基因发生了变化：STAR、c.465+1G>；A和p(E99K)中的复合杂合变体，以及Cyp11a1中的杂合rs6161变化。没有在其他已知原因基因中检测到变异。先证者的母亲是c.465+1G>；A和rs6161 Cyp11a1变异体的杂合子，而父亲是STAR(E99K)突变的纯合子，而Cyp11a1是野生型。短联会试验显示，父母均有正常的肾上腺皮质功能。STAR变异体c.465+1G>；A会导致mRNA外显子4的异常剪接，SIFT和CADD预测的p.(E99K)变异体的增加可能足以引起PAI，但这绝不是确定的，因为未受影响的父亲是后一种变化的纯合子。Rs6161 Cyp11a1变异[c.940G>；A，p.(E314K)]最近被证明与另一个等位基因上严重而罕见的破坏性改变一起导致PAI，然而对Cyp11a1编码区的测序表明这一课题没有进一步的变化。我们想知道这名儿童的孤立性糖皮质激素缺乏的表型是否由于Cyp11a1杂合突变和两个STAR变异体的三等位基因遗传所致，其中每一个变异体都造成了部分功能丧失负担，当两者结合在一起时，足以导致PAI，或者STAR中的c.465+1G>；A功能丧失和假定的部分功能丧失p.(E99K)可能是原因。
An eight-year old South Asian boy presenting with progressive hyperpigmentation was found to have primary adrenal insufficiency (PAI) in the form of isolated glucocorticoid deficiency. Follow up of this boy for nine years, until the age of 17 years showed normal pubertal onset and progression. Molecular evaluation, by targeted next generation sequencing of candidate genes linked to PAI revealed changes in two genes that are intricately linked in the early stages of steroid biosynthesis: compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous rs6161 change in CYP11A1. No variants in other known causal genes were detected. The proband’s mother was heterozygous for the c.465+1G>A STAR and rs6161 CYP11A1 variants, while the father was homozygous for the p.(E99K) alteration in STAR but wild-type for CYP11A1. Both parents had normal adrenal cortical function as revealed by short Synacthen tests. The STAR variant c.465+1G>A will lead to abnormal splicing of exon 4 in mRNA and the addition of the p.(E99K) variant, predicted damaging by SIFT and CADD, may be sufficient to cause PAI but this is by no means certain given that the unaffected father is homozygous for the latter change. The rs6161 CYP11A1 variant [c.940G>A, p.(E314K)] has recently been demonstrated to cause PAI in conjunction with a severe rare disruptive change on the other allele, however sequencing of the coding region of CYP11A1 revealed no further changes in this subject. We wondered whether the phenotype of isolated glucocorticoid deficiency had arisen in this child due to tri-allelic inheritance of a heterozygous CYP11A1 change along with the two STAR variants each of which contribute a partial loss-of-function burden that, when combined, is sufficient to cause PAI or if the loss-of-function c.465+1G>A combined with the presumed partial loss-of-function p.(E99K) in STAR could be causative.
登录
查看更多内容
DOI：
10.1210/jc.2015-3250
发表时间：
2016-01
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
Guran T;Buonocore F;Saka N;Ozbek MN;Aycan Z;Bereket A;Bas F;Darcan S;Bideci A;Guven A;Demir K;Akinci A;Buyukinan M;Aydin BK;Turan S;Agladioglu SY;Atay Z;Abali ZY;Tarim O;Catli G;Yuksel B;Akcay T;Yildiz M;Ozen S;Doger E;Demirbilek H;Ucar A;Isik E;Ozhan B;Bolu S;Ozgen IT;Suntharalingham JP;Achermann JC
通讯作者：
Achermann JC
影响因子：
4.1
作者：
Buonocore F;Maharaj A;Qamar Y;Koehler K;Suntharalingham JP;Chan LF;Ferraz-de-Souza B;Hughes CR;Lin L;Prasad R;Allgrove J;Andrews ET;Buchanan CR;Cheetham TD;Crowne EC;Davies JH;Gregory JW;Hindmarsh PC;Hulse T;Krone NP;Shah P;Shaikh MG;Roberts C;Clayton PE;Dattani MT;Thomas NS;Huebner A;Clark AJ;Metherell LA;Achermann JC
通讯作者：
Achermann JC
DOI：
10.1172/jci90171
发表时间：
2017-03-01
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Prasad R;Hadjidemetriou I;Maharaj A;Meimaridou E;Buonocore F;Saleem M;Hurcombe J;Bierzynska A;Barbagelata E;Bergadá I;Cassinelli H;Das U;Krone R;Hacihamdioglu B;Sari E;Yesilkaya E;Storr HL;Clemente M;Fernandez-Cancio M;Camats N;Ram N;Achermann JC;Van Veldhoven PP;Guasti L;Braslavsky D;Guran T;Metherell LA
通讯作者：
Metherell LA
影响因子：
15.9
作者：
Gineau, Laure;Cognet, Celine;Jouanguy, Emmanuelle
通讯作者：
Jouanguy, Emmanuelle
影响因子：
5.8
作者：
Bose, HS;Sato, S;Miller, WL
通讯作者：
Miller, WL