Loss of nephrocystin-3 function can cause embryonic lethality, meckel-gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia
Loss of nephrocystin-3 function can cause embryonic lethality, meckel-gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia
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DOI：
10.1016/j.ajhg.2008.02.017
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发表时间：
2008-04-01
影响因子：
9.8
通讯作者：
Omran, Heymut
中科院分区：
文献类型：
--
作者：
Bergmann, Carsten;Fliegauf, Manfred;Omran, Heymut
许多遗传性疾病与初级纤毛功能障碍有关，初级纤毛几乎普遍存在于体内，并作为单独的细胞机械感觉细胞器。纤毛相关疾病（纤毛病）（如肾单位营养不良）的临床表现和受累组织列表很广，并归因于纤毛蛋白的广泛表达模式。然而，人们对导致这种戏剧性多样性的表型的分子机制知之甚少。我们最近报道了在儿童和年轻人孤立性肾单位营养不良和相关的肝纤维化或视网膜毡层变性的低形态NPHP 3突变。在这里，我们选择了在小鼠和人类中的组合方法来定义NPHP 3/Nphp 3突变的表型谱和肾囊蛋白-3蛋白的作用。我们证明，pcy突变产生一个亚型Nphp 3等位基因，负责囊性肾病表型，而Nphp 3功能的完全丧失导致原位逆位，先天性心脏病，小鼠胚胎致死。在人类中，我们发现NPHP 3突变可以引起广泛的早期胚胎图案缺陷的临床谱，包括原位逆位，多指（趾）畸形，中枢神经系统畸形，结构性心脏缺陷，耳前瘘管，以及广泛的先天性肾脏和泌尿道异常（CAKUT）。在功能水平上，我们发现，肾囊蛋白-3直接与inversin相互作用，可以抑制像inversin典型的Writ信号，而肾囊蛋白-3缺乏导致非洲爪蟾典型的平面细胞极性缺陷，这表明在控制典型和非典型（平面细胞极性）Writ信号的作用。
Many genetic diseases have been linked to the dysfunction of primary cilia, which occur nearly ubiquitously in the body and act as solitary cellular mechanosensory organelles. The list of clinical manifestations and affected tissues in cilia-related disorders (ciliopathies) such as nephronophthisis is broad and has been attributed to the wide expression pattern of ciliary proteins. However, little is known about the molecular mechanisms leading to this dramatic diversity of phenotypes. We recently reported hypomorpoic NPHP3 mutations in children and young adults with isolated nephronophthisis and associated hepatic fibrosis or tapetoretinal degeneration. Here, we chose a combinatorial approach in mice and humans to define the phenotypic spectrum of NPHP3/Nphp3 mutations and the role of the nephrocystin-3 protein. We demonstrate that the pcy mutation generates a hypomorphic Nphp3 allele that is responsible for the cystic kidney disease phenotype, whereas complete loss of Nphp3 function results in situs inversus, congenital heart defects, and embryonic lethality in mice. In humans, we show that NPHP3 mutations can cause a broad clinical spectrum of early embryonic patterning defects comprising situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulas, and a wide range of congenital anomalies of the kidney and urinary tract (CAKUT). On the functional level, we show that nephrocystin-3 directly interacts with inversin and can inhibit like inversin canonical Writ signaling, whereas nephrocystin-3 deficiency leads in Xenopus laevis to typical planar cell polarity defects, suggesting a role in the control of canonical and noncanonical (planar cell polarity) Writ signaling.