High prevalence of SLC6A8 deficiency in X-linked mental retardation
High prevalence of SLC6A8 deficiency in X-linked mental retardation
复制标题
DOI：
10.1086/422102
复制
发表时间：
2004-07-01
影响因子：
9.8
通讯作者：
Salomons, GS
中科院分区：
文献类型：
--
作者：
Rosenberg, EH;Almeida, LS;Salomons, GS
最近发现了一种新的X连锁精神发育迟滞（XLMR）综合征，由肌酸转运蛋白基因SLC 6A 8突变引起的大脑肌酸缺乏引起。我们研究了SLC 6A 8突变在欧洲XLMR联盟存档的290例非综合征性XLMR患者中的患病率。通过DNA序列分析，研究了SLC 6A 8基因的全长开放阅读框和剪接位点。在总共288例XLMR患者中发现了6种致病性突变，其中5种为新突变，患病率至少为2.1%（6/288）。新的致病突变是一个无义突变（p.Y317X）和四个错义突变。根据保守性、分离性、相关残基的化学性质以及276个对照中不存在这些和任何其他错义突变，得出三个错义突变（p.G87R、p.P390L和p.P554L）是致病性的结论。对于p.C337W突变，可获得额外的材料以生物化学证明（即，通过增加的尿肌酸：肌酐比率）致病性。此外，我们发现了9个新的多态性（IVS 1 + 26 G-->A、IVS 7 + 37 G-->A、IVS 7 + 87 A-->G、IVS 7 - 35 G-->A、IVS 12 -3C-->T、IVS 2 + 88 G-->C、IVS 9 - 36 G-->A、IVS 12 - 82 G-->C和p.Y498），这些多态性存在于XLMR组和/或对照组中。两个错义变体（p.V629I和p.M560V），它们不是高度保守的，与肌酸增加无关：肌酐比值，一种翻译沉默变体（p.L472）和10个间插序列变体或非翻译区变体（IVS6+9C-->T，IVS7-151_152delGA，IVS7-99C-->A，IVS8-35G-->A，IVS8+28C--> T，IVS10-18C-->T，IVS11+21G-->A，IVS12+15C-->T，*207G-->C，IVS 12 + 32 C-->A）仅在XLMR组中发现，但应被视为未分类的变体或多态性（p.M560V）。我们的数据表明，SLC 6A 8突变的频率在XLMR人口接近CGG扩展FMR 1，基因负责脆性X综合征。
A novel X-linked mental retardation (XLMR) syndrome was recently identified, resulting from creatine deficiency in the brain caused by mutations in the creatine transporter gene, SLC6A8. We have studied the prevalence of SLC6A8 mutations in a panel of 290 patients with nonsyndromic XLMR archived by the European XLMR Consortium. The full-length open reading frame and splice sites of the SLC6A8 gene were investigated by DNA sequence analysis. Six pathogenic mutations, of which five were novel, were identified in a total of 288 patients with XLMR, showing a prevalence of at least 2.1% (6/288). The novel pathogenic mutations are a nonsense mutation (p.Y317X) and four missense mutations. Three missense mutations (p. G87R, p. P390L, and p. P554L) were concluded to be pathogenic on the basis of conservation, segregation, chemical properties of the residues involved, as well as the absence of these and any other missense mutation in 276 controls. For the p. C337W mutation, additional material was available to biochemically prove (i.e., by increased urinary creatine: creatinine ratio) pathogenicity. In addition, we found nine novel polymorphisms (IVS1+26G-->A, IVS7+37G-->A, IVS7+ 87A-->G, IVS7-35G-->A, IVS12-3C-->T, IVS2+88G-->C, IVS9-36G-->A, IVS12-82G-->C, and p. Y498) that were present in the XLMR panel and/or in the control panel. Two missense variants (p.V629I and p. M560V) that were not highly conserved and were not associated with increased creatine: creatinine ratio, one translational silent variant (p.L472), and 10 intervening sequence variants or untranslated region variants (IVS6+9C-->T, IVS7-151_152delGA, IVS7-99C-->A, IVS8-35G-->A, IVS8+28C-->T, IVS10-18C-->T, IVS11+21G-->A, IVS12+15C-->T, *207G-->C, IVS12+32C-->A) were found only in the XLMR panel but should be considered as unclassified variants or as a polymorphism (p.M560V). Our data indicate that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1, the gene responsible for fragile-X syndrome.