Tuthill A, Semple R K, Day R, Soos M A, Sweeney E, Seymour P J, Didi M, O'rahilly S
University of Cambridge Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK.
Clin Endocrinol (Oxf). 2007 Jan;66(1):21-6. doi: 10.1111/j.1365-2265.2006.02678.x.
OBJECTIVE/PATIENTS: Rabson-Mendenhall syndrome (RMS) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene. We have identified a pair of siblings with RMS attributable to compound heterozygosity for two insulin receptor mutations, one previously unreported, and have characterized the novel receptor mutation functionally.
Insulin receptor sequencing was performed to identify the mutations. Expression levels of the mature receptor were determined in lymphoblastoid cells from the affected subjects. Further studies of immortalized cell lines transfected with mutant and wild type (WT) receptors were undertaken to characterize the effects of the novel mutation on [(125)I]-labelled insulin binding, proreceptor processing and insulin-stimulated receptor autophosphorylation.
Sequencing of the insulin proreceptor coding sequence revealed both siblings to be compound heterozygotes for the missense mutations Arg209His and Gly359Ser in the mature insulin receptor. The former mutation has been described in homozygous form in Donohue syndrome, while the latter is novel. Insulin receptor expression in lymphoblastoid cell lines was present at only 10-30% of that in control cells; studies of immortalized cells transfected with mutant and WT receptors confirmed the reduced expression of the mutant. The degree of impairment of insulin binding and insulin-stimulated receptor autophosphorylation were commensurate with the decrease in expression of the mature receptor.
Loss of function of the novel insulin receptor (INSR) G359S variant is largely accounted for by aberrant proreceptor processing rather than intrinsically impaired signal transduction by the mutant receptor.
目的/患者：拉布森 - 门登霍尔综合征（RMS）是一种罕见的、隐性遗传的极端胰岛素抵抗疾病，由胰岛素受体基因突变引起。我们鉴定出一对患有RMS的同胞兄妹，他们因胰岛素受体的两个突变（其中一个此前未报道）而呈复合杂合状态，并对该新的受体突变进行了功能表征。
进行胰岛素受体测序以鉴定突变。测定了患病受试者淋巴母细胞系中成熟受体的表达水平。对转染了突变型和野生型（WT）受体的永生化细胞系进行了进一步研究，以表征该新突变对[¹²⁵I]标记胰岛素结合、前受体加工及胰岛素刺激的受体自身磷酸化的影响。
胰岛素前受体编码序列测序显示，这对同胞兄妹在成熟胰岛素受体中均为错义突变Arg209His和Gly359Ser的复合杂合子。前一个突变已在多诺霍综合征的纯合形式中被描述，而后一个是新的。淋巴母细胞系中的胰岛素受体表达仅为对照细胞的10% - 30%；对转染了突变型和WT受体的永生化细胞的研究证实了突变体表达降低。胰岛素结合和胰岛素刺激的受体自身磷酸化的受损程度与成熟受体表达的降低程度相当。
新的胰岛素受体（INSR）G359S变体的功能丧失主要是由于前受体加工异常，而非突变受体本身信号转导受损。
