Demir Korcan, Yildiz Melek, Bahat Hilla, Goldman Michael, Hassan Nisreen, Tzur Shay, Ofir Ayala, Magen Daniella
Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylül University, Turkey.
Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Hospital, Turkey.
J Clin Endocrinol Metab. 2017 Dec 1;102(12):4604-4614. doi: 10.1210/jc.2017-01592.
NaPi-IIa, encoded by SLC34A1, is a key phosphate transporter in the mammalian proximal tubule and plays a cardinal role in renal phosphate handling. NaPi-IIa impairment has been linked to various overlapping clinical syndromes, including hypophosphatemic nephrolithiasis with osteoporosis, renal Fanconi syndrome with chronic kidney disease, and, most recently, idiopathic infantile hypercalcemia and nephrocalcinosis.
We studied the molecular basis of idiopathic infantile hypercalcemia with partial proximal tubulopathy in two apparently unrelated patients of Israeli and Turkish descent.
Genetic analysis in two affected children and their close relatives was performed using whole-exome sequencing, followed by in vitro localization and trafficking analysis of mutant NaPi-IIa.
Mutation and haplotype analyses in both patients revealed a previously described homozygous loss-of-function inserted duplication (p.I154_V160dup) in NaPi-IIa, which is inherited identical-by-descent from a common ancestor. The shared mutation was originally reported by our team in two adult siblings with renal Fanconi syndrome, hypophosphatemic bone disease, and progressive renal failure who are family members of one of the infants reported herein. In vitro localization assays and biochemical analysis of p.I154_V160dup and of additional NaPi-IIa mutants harboring a trafficking defect indicate aberrant retention at the endoplasmic reticulum in an immature and underglycosylated state, leading to premature proteasomal degradation.
Our findings expand the phenotypic spectrum of NaPi-IIa disruption, reinforce its link with proximal tubular impairment, enable longitudinal study of the natural history of the disease, and shed light on cellular pathways associated with loss of function and impaired trafficking of NaPi-IIa mutants.
由SLC34A1编码的IIa型钠-磷协同转运蛋白（NaPi-IIa）是哺乳动物近端小管中的关键磷酸盐转运体，在肾脏磷酸盐处理中起主要作用。NaPi-IIa功能障碍与多种重叠的临床综合征有关，包括伴有骨质疏松症的低磷性肾结石、伴有慢性肾病的肾性范科尼综合征，以及最近发现的特发性婴儿高钙血症和肾钙质沉着症。
我们研究了两名来自以色列和土耳其血统、明显无亲缘关系的患者发生的伴有部分近端小管病变的特发性婴儿高钙血症的分子基础。
对两名患病儿童及其近亲进行全外显子组测序，随后对突变型NaPi-IIa进行体外定位和转运分析。
两名患者的突变和单倍型分析均显示，NaPi-IIa中存在先前描述的纯合功能丧失插入重复突变（p.I154_V160dup），该突变是从一个共同祖先遗传而来的同宗同源突变。我们团队最初在两名患有肾性范科尼综合征、低磷性骨病和进行性肾衰竭的成年同胞中报道了这种共同突变，他们是本文报道的其中一名婴儿的家庭成员。对p.I154_V160dup以及其他存在转运缺陷的NaPi-IIa突变体进行的体外定位分析和生化分析表明，这些突变体在内质网中以未成熟和低糖基化状态异常滞留，导致过早的蛋白酶体降解。
我们的研究结果扩展了NaPi-IIa破坏的表型谱，加强了其与近端小管损伤的联系，能够对该疾病的自然史进行纵向研究，并揭示了与NaPi-IIa突变体功能丧失和转运受损相关的细胞途径。
