肌苷一磷酸脱氢酶1基因的突变(IMPDH1)导致RP10形式的常染色体显性遗传视网膜色素变性。
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Bowne SJ,沙利文LS,布兰顿SH Cepko CL,街”年代,桦树DG, Hughbanks-Wheaton D, Heckenlively JR, Daiger SP
肌苷一磷酸脱氢酶1基因的突变(IMPDH1)导致RP10形式的常染色体显性遗传视网膜色素变性。
哼摩尔麝猫。2002年3月1;11 (5):559 - 68。
- PubMed ID
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11875050 (在PubMed]
- 文摘
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常染色体显性遗传视网膜色素变性(adRP)是一组异构的累进性视网膜病变引起的几个不同的基因。一个轨迹,RP10 adRP,映射到人类染色体7 q31.1可能占5 - 10%的adRP情况下在美国和欧洲。我们确定了两个美国家庭RP10 adRP形式通过链接映射和使用这些家庭减少连杆之间的间隔为3.45 Mb侧翼标记D7S686 RP-STR8。基因序列和转录分析确定了54个独立在这个地区,其中至少10 retinal-expressed因此候选人RP10基因。正常小鼠的视网膜屏幕的成绩单比较视网膜从crx视网膜- / crx基因敲除小鼠(低分化光感受器)演示了一个倍减少一个候选人,肌苷一磷酸脱氢酶1 (IMPDH1;EC 1.1.1.205)。因为许多已知的基因导致感光细胞,色素性视网膜炎CRX控制IMPDH1成了一个高优先级的突变筛选候选人。DNA测序的影响个人从两名美国RP10家庭显示GAC - - > AAC过渡密码子226替换为天冬氨酸天冬酰胺在两个家庭。相同的突变被发现在英国RP10家庭。的Asp226Asn错义突变出现在所有受影响的个人测试和缺席控制的影响。 The aspartic acid at codon 226 is conserved in all IMPDH genes, in all species examined, including bacteria, suggesting that this mutation is highly deleterious. Subsequent screening of probands from 60 other adRP families revealed an additional family with this mutation, confirming its association with retinitis pigmentosa and the relatively high frequency of this mutation. Another IMPDH1 substitution, Val268Ile, was also observed in this cohort of patients but not in controls. IMPDH1 is a ubiquitously expressed enzyme, functioning as a homotetramer, which catalyzed the rate-limiting step in de novo synthesis of guanine nucleotides. As such, it plays an important role in cyclic nucleoside metabolism within photoreceptors. Several classes of drugs are known to affect IMPDH isoenzymes, including nucleotide and NAD analogs, suggesting that small-molecule therapy may be available, one day, for RP10 patients.