Contrasting effects of ENU induced embryonic lethal mutations of the quaking gene
Contrasting effects of ENU induced embryonic lethal mutations of the quaking gene
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DOI：
10.1006/geno.1999.5804
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发表时间：
1999-05-01
期刊：
影响因子：
4.4
通讯作者：
Dove, WF
中科院分区：
文献类型：
--
作者：
Cox, RD;Hugill, A;Dove, WF
震动（qk）基因的多个等位基因具有多种表型，其严重程度从早期胚胎死亡到可存活的髓鞘发育异常不等。先前的一项研究发现了一个候选基因QKI，它包含一个rna结合结构域，并编码至少三种蛋白质亚型（QKI-5、-6和-7）。我们已经确定了QKI的基因组结构，在cdna中确定了一个额外的替代端。我们进一步研究了致死性等位基因qk（l-1）、qk（kt1）、qk（k2）和qk（kt3）突变的外显子和剪接位点。qk（l-1）的突变在QKI-6异构体的末端外显子上产生了一个剪接位点，qk（k2）和qk（kt3）中KH结构域和QUA1结构域的错义突变表明这些结构域具有重要的功能。虽然每个ENU诱导的等位基因的纯合子作为胚胎死亡，但它们作为具有qk(v)的可活复合杂合子的表型不同。携带qk（kt1）、qk（k2）和qk（kt3）的复合杂合qk(u)动物都表现出与qk(u)/qk(u)动物相似的永久震动表型，而qk(u)/qk（l-1）动物只表现出短暂震动表型。qk（l-1）突变消除了QKI-5亚型，表明该亚型在胚胎存活中起着至关重要的作用。在qk(u)/qk（l-1）小鼠中观察到的瞬时震动表型表明，QKI-6和QKI-7亚型主要在髓鞘形成过程中起作用，但QKI-5可能在早期髓鞘形成中起浓度依赖性作用。该突变分析证明了一系列等位基因在检测复杂基因座功能方面的能力，并表明额外的突变等位基因可以揭示该复杂基因的其他功能。(C) 1999学术出版社。
Multiple alleles of the quaking (qk) gene have a variety of phenotypes ranging in severity from early embryonic death to viable dysmyelination, A previous study identified a candidate gene, QKI, that contains an RNA-binding domain and encodes at least three protein isoforms (QKI-5, -6 and -7). We have determined the genomic structure of QKI, identifying an additional alternative end in cDNAs. Further we have examined the exons and splice sites for mutations in the lethal alleles qk(l-1), qk(kt1), qk(k2), and qk(kt3). The mutation in qk(l-1) creates a splice site in the terminal exon of the QKI-6 isoform, Missense mutations in the KH domain and the QUA1 domains in qk(k2) and qk(kt3), respectively, indicate that these domains are of critical functional importance. Although homozygotes for each ENU induced allele die as embryos, their phenotypes as viable compound heterozygotes with qk(v) differ. Compound heterozygous qk(u) animals carrying qk(kt1), qk(k2),and qk(kt3) all exhibit a permanent quaking phenotype similar to that of qk(u)/qk(u) animals, whereas qk(u)/qk(l-1) animals exhibit only a transient quaking phenotype, The qk(l-1) mutation eliminates the QKI-5 isoform, showing that this isoform plays a crucial role in embryonic survival. The transient quaking phenotype observed in qk(u)/qk(l-1) mice indicates that the QKI-6 and QKI-7 isoforms function primarily during myelination, but that QKI-5 may have a concentration-dependerat role in early myelination. This mutational analysis demonstrates the power of series of alleles to examine the function of complex loci and suggests that additional mutant alleles of quaking could reveal additional functions of this complex gene. (C) 1999 Academic Press.