Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa
Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa
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DOI：
10.1093/hmg/11.5.559
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发表时间：
2002-03-01
影响因子：
3.5
通讯作者：
Daiger, SP
中科院分区：
文献类型：
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作者：
Bowne, SJ;Sullivan, LS;Daiger, SP
常染色体显性视网膜色素变性（adRP）是由几种不同基因引起的异质进行性视网膜病变。其中一个基因座，RP10形式的adRP，位于人类染色体7q31.1，可能占美国人和欧洲人adRP病例的5-10%。我们通过连锁作图鉴定了两个具有RP10型adRP的美国家族，并利用这些家族将侧翼标记D7S686和RP-STR8之间的连锁间隔缩短到3.45 Mb。序列和转录分析鉴定出该区域内54个独立基因，其中至少10个是视黄醛表达的，因此是RP10基因的候选基因。一项比较正常小鼠视网膜和crx-/crx-敲除小鼠视网膜（具有低分化光感受器）的视网膜转录本的筛选显示，其中一个候选物肌苷单磷酸脱氢酶1 （IMPDH1; EC 1.1.1.205）减少了6倍。由于已知导致视网膜色素变性的许多基因在光感受器中受CRX控制，因此IMPDH1成为突变筛选的优先候选基因。对来自两个美国RP10家族的受影响个体的DNA测序显示，两个家族的密码子226中都有GAC- >AAC转换，用天冬酰胺代替天冬氨酸。在一个英国RP10家族中也发现了相同的突变。Asp226Asn错义突变在所有受影响的个体中都存在，而在未受影响的对照组中不存在。密码子226处的天冬氨酸在所有IMPDH基因中都是保守的，在所有被检测的物种中，包括细菌，这表明这种突变是高度有害的。随后对60个其他adRP家族的先证进行筛查，发现另外一个家族有这种突变，证实了它与视网膜色素变性和这种突变的相对高频率有关。另一种IMPDH1替代，Val268Ile，也在该队列患者中观察到，但在对照组中没有。IMPDH1是一种普遍表达的酶，具有同型四聚体的功能，催化了鸟嘌呤核苷酸从头合成的限速步骤。因此，它在光感受器内的环核苷代谢中起重要作用。已知有几类药物会影响IMPDH同工酶，包括核苷酸和NAD类似物，这表明有一天小分子治疗可能对RP10患者有效。
Autosomal dominant retinitis pigmentosa (adRP) is a heterogeneous set of progressive retinopathies caused by several distinct genes. One locus, the RP10 form of adRP, maps to human chromosome 7q31.1 and may account for 5-10% of adRP cases among Americans and Europeans. We identified two American families with the RP10 form of adRP by linkage mapping and used these families to reduce the linkage interval to 3.45 Mb between the flanking markers D7S686 and RP-STR8. Sequence and transcript analysis identified 54 independent genes within this region, at least 10 of which are retinal-expressed and thus candidates for the RP10 gene. A screen of retinal transcripts comparing retinas from normal mice to retinas from crx-/crx- knockout mice (with poorly differentiated photoreceptors) demonstrated a 6-fold reduction in one candidate, inosine monophosphate dehydrogenase 1 (IMPDH1; EC 1.1.1.205). Since many of the genes known to cause retinitis pigmentosa are under CRX control in photoreceptors, IMPDH1 became a high-priority candidate for mutation screening. DNA sequencing of affected individuals from the two American RP10 families revealed a GAC-->AAC transition in codon 226 substituting an asparagine for an aspartic acid in both families. The identical mutation was also found in a British RP10 family. The Asp226Asn missense mutation is present in all affected individuals tested and absent from unaffected controls. 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 isoezymes, including nucleotide and NAD analogs, suggesting that small-molecule therapy may be available, one day, for RP10 patients.