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Abstract：
Ciliopathies are a class of inherited severe human disorders that occur due to defective formation or function of cilia. The RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein1-like) gene encodes for a ciliary protein involved in regulating cilia formation and function. Mutations in RPGRIP1L cause ciliopathies associated with severe embryonic defects, such as Meckel-Gruber Syndrome (MKS). Here we report RPGRIP1L mutation analysis in a family diagnosed with MKS. The clinical manifestations of the fetus included thoraco-lumbar open neural tube defect with associated Chiari type II malformation and hydrocephalus, bilateral club feet, and single right kidney/ureter. Analysis of the parental DNA samples revealed that the father carried a previously reported mutation R1236C/+ whereas the mother had a novel splice site mutation IVS6+1 G > A/+ in RPGRIP1L. The splice site mutation resulted in the exclusion of in-frame exon 6 of RPGRIP1L (RPGRIP1L-∆Ex6) but expressed a stable protein in fibroblasts derived from the parents\' skin biopsies. The GFP-RPGRIP1L-∆Ex6 mutant protein exhibited relatively reduced ciliary localization in transiently-transfected cultured RPE-1 cells. Taken together, this study identifies a novel RPGRIP1L variant RPGRIP1L-∆Ex6, which in combination with RPGRIP1L-R1236C is associated with MKS. We also suggest that the deletion of exon 6 of RPGRIP1L leads to reduced ciliary localization of RPGRIP1L, indicating a plausible mechanism of associated disease.
摘要：
纤毛病是一类由于纤毛的缺陷形成或功能而发生的遗传性严重人类疾病。RPGRIP1L（视网膜色素变性GTPase调节因子相互作用蛋白1样）基因编码参与调节纤毛形成和功能的纤毛蛋白。RPGRIP1L的突变导致与严重胚胎缺陷相关的纤毛病变，例如Meckel-Gruber综合征(MKS)。在这里，我们报告了一个诊断为MKS的家族中的RPGRIP1L突变分析。胎儿的临床表现包括胸腰段开放性神经管缺损合并ChiariⅡ型畸形和脑积水,双侧球杆脚,和单个右肾/输尿管。对亲本DNA样品的分析表明，父亲携带先前报道的突变R1236C/，而母亲在RPGRIP1L中具有新的剪接位点突变IVS61G>A/。剪接位点突变导致RPGRIP1L的框内外显子6被排除（RPGRIP1L-ΔEx6），但在源自父母皮肤活检的成纤维细胞中表达稳定的蛋白。在瞬时转染的培养的RPE-1细胞中，GFP-RPGRIP1L-ΔEx6突变蛋白表现出相对减少的纤毛定位。一起来看,这项研究鉴定了一种新的RPGRIP1L变体RPGRIP1L-ΔEx6，它与RPGRIP1L-R1236C组合与MKS相关。我们还建议RPGRIP1L外显子6的缺失导致RPGRIP1L纤毛定位减少，表明相关疾病的合理机制。
