SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis
SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis
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DOI：
10.1086/499409
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发表时间：
2006-02-01
影响因子：
9.8
通讯作者：
Jüppner, H
中科院分区：
文献类型：
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作者：
Bergwitz, C;Roslin, NM;Jüppner, H
遗传性低磷血症佝偻病伴高钙尿症（HHRH）是一种罕见的常染色体隐性遗传疾病，首次在一个大血缘贝都因人家族中被描述。HHRH的特征是继发于肾磷酸盐消耗的低磷血症、佝偻病、肢体畸形、肌肉无力和骨痛的影像学和/或组织学证据。HHRH不同于其他形式的低磷血症佝偻病，因为受影响的个体由于血清1,25-二羟基维生素D水平升高和肠道钙吸收增加而出现高钙尿。我们进行了全基因组连锁扫描，结合纯合子作图，使用了来自一个大血缘贝都因亲属的基因组DNA，其中包括10名被诊断为HHRH的患者。该疾病定位于染色体9q34上一个1.6 mbp的区域，该区域含有SLC34A3，该基因编码肾磷酸钠共转运体NaPi-IIc。核苷酸序列分析显示，该候选基因在所有受HHRH影响的个体中存在纯合单核苷酸缺失（c. 228delC）。预计该突变将截断第一个跨膜结构域的NaPi-IIc蛋白，因此可能导致该蛋白在c. 228delC纯合个体中完全丧失功能。此外，在另外3个不相关的HHRH类群中发现了复合杂合错义和缺失突变，支持了该疾病由同时影响两个等位基因的SLC34A3突变引起的结论。SLC34A3杂合突变的个体经常出现高钙尿症，通常与轻度低磷血症和/或1,25-二羟基维生素D水平升高有关。我们得出结论，NaPi-IIc在调节磷酸盐稳态中起关键作用。
Hereditary hypophosphatemic rickets with hypercalciuria ( HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaPi-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion ( c. 228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaPi-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c. 228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaPi-IIc has a key role in the regulation of phosphate homeostasis.