Kosugi S, Ban T, Akamizu T, Valente W, Kohn L D
Cell Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
J Clin Endocrinol Metab. 1993 Jul;77(1):19-24. doi: 10.1210/jcem.77.1.8100829.
Deletions of residues 295-306, 299-301, and 387-395 of the TSH receptor, as well as point mutations of cysteine 301 or 390 to serine, and tyrosine 385 to phenylalanine or alanine, markedly diminish the ability of a transfected receptor to measure the activity of blocking TSH receptor autoantibodies (TSHRAbs) in patients with idiopathic myxedema and hypothyroidism, but not stimulating TSHRAbs in Graves' patients. This has allowed us to use these mutants to detect stimulating TSHRAb activity in the sera of hypothyroid patients with idiopathic myxedema who have blocking TSHRAbs. In 7 such patients, we show that 50% or more have significant stimulatory activity in cells transfected with mutant receptors, as evidenced by the ability of the immunoglobulin G to directly increase cAMP levels or to enhance the ability of TSH or a Graves' stimulating TSHRAb to increase cAMP levels. Three of the TSH receptor mutants, deletions of residues 295-306 and 387-395 and the point mutation of cysteine 301 to serine, are shown to be particularly useful in these assays and may be useful to clarify the pathogenetic role and clinical significance of stimulating TSHRAbs in patients with autoimmune thyroid disease who also have blocking TSHRAbs.
促甲状腺激素（TSH）受体的295 - 306位、299 - 301位和387 - 395位残基缺失，以及半胱氨酸301或390突变为丝氨酸、酪氨酸385突变为苯丙氨酸或丙氨酸，显著降低了转染受体测量特发性黏液性水肿和甲状腺功能减退患者中阻断性促甲状腺激素受体自身抗体（TSHRAbs）活性的能力，但对格雷夫斯病患者中刺激性TSHRAbs的测量能力无影响。这使我们能够利用这些突变体检测患有阻断性TSHRAbs的特发性黏液性水肿甲状腺功能减退患者血清中的刺激性TSHRAb活性。在7例此类患者中，我们发现50%或更多患者在用突变体受体转染的细胞中具有显著的刺激活性，免疫球蛋白G直接增加环磷酸腺苷（cAMP）水平或增强促甲状腺激素或格雷夫斯病刺激性TSHRAb增加cAMP水平的能力可证明这一点。促甲状腺激素受体的三个突变体，即295 - 306位和387 - 395位残基缺失以及半胱氨酸301突变为丝氨酸的点突变，在这些检测中显示特别有用，可能有助于阐明在同时患有阻断性TSHRAbs的自身免疫性甲状腺疾病患者中刺激性TSHRAbs的致病作用和临床意义。
