Endocrine Unit, Attikon University Hospital, Athens University Medical School, Second Department of Internal Medicine-Research Institute and Diabetes Center, 1 Rimini Street, Haidari, Athens 12462, Greece.
J Clin Endocrinol Metab. 2012 Nov;97(11):4260-7. doi: 10.1210/jc.2012-2467. Epub 2012 Sep 4.
Corticosteroid-binding globulin (CBG), encoded by SERPINA6, is the principal plasma binding protein for cortisol. Most nonsynonymous single-nucleotide polymorphisms that alter the production or function of CBG occur rarely, and their clinical significance remains obscure.
Serum and DNA were obtained from a Greek woman with low morning cortisol levels and from family members. SERPINA6 exons were sequenced, and serum CBG was measured by ELISA and cortisol-binding capacity assay. Recombinant CBG variants were produced for detailed functional studies.
A novel heterozygous c.1282G>C transversion in exon 5 of SERPINA6, resulting in a p.Trp393Ser (W371S) substitution, was identified in the proband, who was also heterozygous for single-nucleotide polymorphisms encoding the CBG Lyon (D367N) and CBG A224S variants. The proband had no measurable plasma cortisol-binding activity despite a CBG level of 273 nm by ELISA. She inherited CBG W371S from her mother whose plasma cortisol-binding capacity was approximately 50% lower than the CBG measurements by ELISA (314 nm). The proband's father and four children were heterozygous for CBG D367N; their CBG levels by ELISA were normal, but corresponding cortisol-binding capacity measurements were 50% lower. Pedigree analysis revealed that W371S segregates with A224 and that D367N and W371S segregate separately. Recombinant CBG D367N and CBG W371S had no measureable cortisol-binding activity.
A new CBG Athens (W371S) variant that lacks cortisol-binding activity has been identified in a carrier of the cortisol-binding deficient CBG Lyon (D367N) variant. Analyses of CBG levels in this pedigree illustrate how immunoassays fail to accurately reflect cortisol-binding activity.
皮质类固醇结合球蛋白（CBG）由 SERPINA6 编码，是皮质醇的主要血浆结合蛋白。大多数改变 CBG 产生或功能的非同义单核苷酸多态性很少发生，其临床意义仍不清楚。
从一名早晨皮质醇水平较低的希腊女性及其家庭成员中获得血清和 DNA。对 SERPINA6 外显子进行测序，并通过 ELISA 和皮质醇结合能力测定法测定血清 CBG。为了进行详细的功能研究，产生了重组 CBG 变体。
在该先证者中发现了 SERPINA6 外显子 5 中的 novel 杂合 c.1282G>C 颠换，导致 p.Trp393Ser（W371S）取代，该先证者还携带编码 CBG Lyon（D367N）和 CBG A224S 变体的单核苷酸多态性。尽管 ELISA 检测到的 CBG 水平为 273nm，但该先证者没有可测量的血浆皮质醇结合活性。她从其母亲那里继承了 CBG W371S，其血浆皮质醇结合能力比 ELISA（314nm）测量的 CBG 低约 50%。先证者的父亲和四个孩子均为 CBG D367N 杂合子；他们的 ELISA 检测到的 CBG 水平正常，但相应的皮质醇结合能力检测值低 50%。家系分析表明，W371S 与 A224 共分离，而 D367N 和 W371S 分别共分离。重组 CBG D367N 和 CBG W371S 没有可测量的皮质醇结合活性。
在皮质醇结合缺陷的 CBG Lyon（D367N）变体的携带者中，已经发现了一种新的缺乏皮质醇结合活性的 CBG Athens（W371S）变体。对该家系中 CBG 水平的分析说明了免疫测定法如何不能准确反映皮质醇结合活性。
