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Abstract：
WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.
摘要：
含WD40重复序列的蛋白质形成存在于所有真核生物中的蛋白质大家族。这里,我们在编码WD40重复蛋白家族成员的WDR37中鉴定出5个具有从头变异的儿童先证者.两个先证者共有一个变体,而其他的在WD40重复之外的附近氨基酸中具有变体。先证者表现出共同的癫痫表型，结肠瘤,面部畸形让人联想到CHARGE综合征，发育迟缓和智力残疾，和小脑发育不全.WDR37蛋白在脊椎动物和无脊椎动物模型生物中高度保守,并且目前与人类疾病无关。我们生成了单个果蝇直系同源的无效等位基因，以获得功能见解，并用GAL4替换了果蝇基因CG12333/wdr37的编码区。这些果蝇是纯合的，但表现出严重的爆炸敏感性，与果蝇癫痫发作相关的表型。此外,突变的苍蝇在爬上小瓶的墙壁时掉落，表明握力有缺陷，重复爬升和下降的循环。类似于墙壁粘附缺陷，突变的男性在交配过程中经常失去对女性腹部的控制。通过使用CG12333/wdr37基因座中的GAL4驱动UAS-人参考WDR37cDNA来拯救这些表型。在三个人类受试者中发现的两个变体未能挽救这些表型，表明这些等位基因严重影响了这种蛋白质的功能。一起来看,我们的数据提示,WDR37变异是一种新的综合征性神经系统疾病的基础.
