Four families with loss of function mutations of the thyrotropin receptor
Four families with loss of function mutations of the thyrotropin receptor
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DOI：
10.1210/jc.81.12.4229
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发表时间：
1996-12-01
影响因子：
5.8
通讯作者：
Milgrom, E
中科院分区：
文献类型：
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作者：
deRoux, N;Misrahi, M;Milgrom, E
我们观察到四个家庭的TSH受体基因的功能缺失突变。1例患者为纯合子Pro（162）Ala置换。其余3种为复合杂合子：1）Gln（324）→ Stop和Asp（410）Asn（2）），Cys（41）Ser和Phe（525）Leu，3）Cys（390）Trp和Trp（546）→ Stop。杂合子父母的TSH水平正常。这些结果证实了TSH受体缺陷的隐性特征，在转染的COS-7细胞中表达的各种突变受体表明其功能受损。我们通过免疫荧光研究了细胞表面受体的表达，它们结合激素的能力，以及它们激活腺苷酸环化酶的能力。一些突变使我们能够确定对受体功能特别重要的位点。取代Cys（390）Trp消除高亲和力激素结合。Asp（410）Asn突变的受体与激素结合正常，但不能激活腺苷酸环化酶。这一结果强调了这种酸性胞外残基在信号传递中的作用，靠近第一个跨膜片段。Phe（525）Leu取代也明显损害腺苷酸环化酶的激活，强调了第二个细胞内环在受体信号传导中的重要性。
We observed four families with loss of function mutations of the TSH receptor gene. One patient had a homozygous Pro(162) Ala substitution. The three other were compound heterozygotes: 1) Gln(324)-->Stop and Asp(410) Asn(2)), Cys(41) Ser and Phe(525) Leu, 3) Cys(390) Trp and Trp(546)-->Stop.In all patients, the plasma TSH concentration was increased, whereas T-3 and T-4 concentrations were normal. The TSH levels were normal in the heterozygous parents. These results confirmed the recessive character of TSH receptor defects.Expression of the various mutated receptors in transfected COS-7 cells demonstrated the impairment of their function. We studied the expression of the receptors on the cell surface by immunofluorescence, their ability to bind hormone, and their capacity to activate adenylate cyclase. Some mutations allowed us to identify sites that are especially important for receptor function. The substitution Cys(390) Trp abolished high affinity hormone binding. Receptor mutated at Asp(410) Asn bound the hormone normally, but failed to activate adenylate cyclase. This result underscores the role of this acidic extracellular residue, close to the first transmembrane segment, in signal transmission. The Phe(525) Leu substitution also markedly impaired adenylate cyclase activation, underlining the importance of the second intracellular loop in receptor signaling.