Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Paediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Med Genet. 2018 Oct;55(10):693-700. doi: 10.1136/jmedgenet-2017-105113. Epub 2018 Jul 30.
Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern.
We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and and mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice.
We found mutations in the insulin receptor substrate 4 () gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary mRNA levels but had unchanged serum thyroid hormone concentrations.
Mutations in are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling.
已发现四种孤立性先天性中枢性甲状腺功能减退症（CeH）的遗传病因，但许多病例仍未得到解释。我们假设存在其他具有孟德尔遗传模式的 CeH 的遗传病因。
我们对两个具有未解释的孤立性 CeH 的家族进行了外显子组测序，随后对无关的特发性 CeH 病例进行了 Sanger 测序。我们对通过家族筛查鉴定的先证者和携带者进行了临床和生化特征分析。我们研究了人下丘脑和垂体组织中的 mRNA 表达，并测量了 Irs4 基因敲除小鼠下丘脑和垂体组织中的血清甲状腺激素和 mRNA 表达。
我们发现两对患有 CeH 的兄弟（一个无义突变，一个移码突变）存在胰岛素受体底物 4（IRS4）基因突变。在 12 例已知基因无变异的无关 CeH 病例中对 IRS4 进行测序，在 3 例患者和 1 例男性同胞中发现了 3 种移码突变（2 种新突变）。所有男性携带者（n=8）均患有游离甲状腺素浓度低于参考区间的 CeH。下丘脑和垂体的 MRI 检查未显示结构异常（n=12）。两名成年男性患者的 24 小时促甲状腺激素（TSH）分泌谱显示基础、脉冲和总 TSH 分泌减少。在人类下丘脑核，包括室旁核，以及垂体中都有表达 mRNA。雌性敲除小鼠的垂体 mRNA 水平降低，但血清甲状腺激素浓度不变。
IRS4 基因突变与男性携带者的孤立性 CeH 相关。由于 IRS4 参与瘦素信号转导，该表型可能与瘦素信号转导中断有关。
