Stitham Jeremiah, Arehart Eric J, Gleim Scott, Douville Karen, MacKenzie Todd, Hwa John
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
Gene. 2007 Jul 1;396(1):180-7. doi: 10.1016/j.gene.2007.03.016. Epub 2007 Apr 1.
The human prostacyclin receptor (hIP) has recently been recognized as an important seven transmembrane G-protein coupled receptor that plays critical roles in atheroprevention and cardioprotection. To date, four non-synonymous genetic variants have been identified, two of which occur at the same Arg amino acid position (R212H, R212C). This observation instigated further genetic screening for prostacyclin receptor variants on 1455 human genomic samples. A total of 31 distinct genetic variants were detected, with 6 (19%) involving Arg residues. Distinct differences in location and frequencies of genetic variants were noted between Caucasian, Asian, Hispanic and African Americans, with the most changes noted in the Asian cohort. From the sequencing results, three Arg-targeted changes at the same 212 position within the third cytoplasmic loop of the human prostacyclin (hIP) receptor were detected: 1) R212C (CGC-->TGC), 2) R212H (CGC-->CAC), and 3) R212R (CGC-->CGT). Three additional Arg codon variants (all exhibiting the same CGC to TGC change) were also detected, R77C, R215C, and R279C. Analysis (GPCR and SNP databases) of 200 other GPCRs, with recorded non-synonymous mutations, confirmed a high frequency of Arg-targeted missense mutations, particularly within the important cytoplasmic domain. Preferential nucleotide changes (at Arg codons), were observed involving cytosine (C) to thymine (T) (pyrimidine to pyrimidine), as well as guanine (G) to adenine (A) (purine to purine) (p<0.001, Pearson's goodness-of-fit test). Such targeting of Arg residues, leading to significant changes in coding amino acid size and/or charge, may have potentially-important structural and evolutionary implications on the hIP and GPCRs in general. In the case of the human prostacyclin receptor, such alterations may reduce the cardio-, vasculo-, and cytoprotective effects of prostacyclin.
人前列环素受体（hIP）最近被认为是一种重要的七跨膜G蛋白偶联受体，在动脉粥样硬化预防和心脏保护中发挥关键作用。迄今为止，已鉴定出四种非同义基因变体，其中两种发生在相同的精氨酸氨基酸位置（R212H、R212C）。这一观察结果促使对1455份人类基因组样本进行前列环素受体变体的进一步基因筛查。共检测到31种不同的基因变体，其中6种（19%）涉及精氨酸残基。在白种人、亚洲人、西班牙裔和非裔美国人之间，基因变体的位置和频率存在明显差异，亚洲人群中变化最为明显。从测序结果中，在人前列环素（hIP）受体第三细胞质环内的相同212位置检测到三个针对精氨酸的变化：1）R212C（CGC→TGC），2）R212H（CGC→CAC），3）R212R（CGC→CGT）。还检测到另外三种精氨酸密码子变体（均表现出相同的CGC到TGC变化），即R77C、R215C和R279C。对200种其他记录了非同义突变的G蛋白偶联受体进行分析（GPCR和SNP数据库），证实了针对精氨酸的错义突变频率很高，尤其是在重要的细胞质结构域内。观察到精氨酸密码子的优先核苷酸变化，涉及胞嘧啶（C）到胸腺嘧啶（T）（嘧啶到嘧啶），以及鸟嘌呤（G）到腺嘌呤（A）（嘌呤到嘌呤）（p<0.001，Pearson拟合优度检验）。这种对精氨酸残基的靶向作用，导致编码氨基酸大小和/或电荷的显著变化，可能对hIP和一般G蛋白偶联受体具有潜在的重要结构和进化意义。就人前列环素受体而言，这种改变可能会降低前列环素的心脏、血管和细胞保护作用。
