Jones Andrew O, Tzenova Jordana, Frappier Danielle, Crumley M Joyce, Roslin Nicole M, Kos Claudine H, Tieder Martin, Langman Craig B, Proesmans Willem, Carpenter Thomas O, Rice Allan, Anderson Donald, Morgan Kenneth, Fujiwara T Mary, Tenenhouse Harriet S
Department of Biology, McGill University, Montreal, Canada.
McGill University Health Centre Research Institute, Montreal, Canada.
J Am Soc Nephrol. 2001 Mar;12(3):507-514. doi: 10.1681/ASN.V123507.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a renal phosphate (Pi) wasting disease first described in an extended Bedouin kindred, is characterized by hypophosphatemia, elevated serum 1,25-dihydroxyvitamin D levels, hypercalciuria, rickets, and osteomalacia. Correction of all abnormalities, except for renal Pi wasting, can be achieved by oral Pi supplementation. These findings and the demonstration that mice that are homozygous for the disrupted Na/Pi cotransporter gene Npt2 exhibit many of the biochemical features of HHRH suggested that mutations in the human orthologue NPT2 might be responsible for HHRH. The NPT2 gene in affected individuals from the Bedouin kindred and four small families was screened for mutations to test this hypothesis. No putative disease-causing mutation was found. Two single nucleotide polymorphisms (SNP), a silent substitution in exon 7 and a nucleotide substitution in intron 4, were identified, and neither consistently segregated with HHRH in the Bedouin kindred. Linkage analysis indicated that the two NPT2 intragenic SNP as well as five microsatellite markers in the NPT2 gene region were not linked to HHRH in the Bedouin kindred. Therefore, this is evidence to exclude NPT2 as a candidate gene for HHRH in the families that were studied.
遗传性低磷性佝偻病伴高钙尿症（HHRH）是一种首先在一个贝都因大家族中被描述的肾性磷酸盐（Pi）消耗性疾病，其特征为低磷血症、血清1,25 - 二羟维生素D水平升高、高钙尿症、佝偻病和骨软化症。除了肾性Pi消耗外，通过口服补充Pi可纠正所有异常情况。这些发现以及破坏钠/磷共转运蛋白基因Npt2的纯合子小鼠表现出许多HHRH生化特征的证明表明，人类同源基因NPT2中的突变可能是HHRH的病因。为了验证这一假设，对来自贝都因大家族和四个小家族的受影响个体的NPT2基因进行了突变筛查。未发现假定的致病突变。鉴定出两个单核苷酸多态性（SNP），一个是外显子7中的沉默替换，另一个是内含子4中的核苷酸替换，且在贝都因大家族中这两个SNP均未与HHRH始终共分离。连锁分析表明，NPT2基因区域中的这两个NPT2基因内SNP以及五个微卫星标记与贝都因大家族中的HHRH不连锁。因此，这一证据排除了NPT2作为所研究家族中HHRH候选基因的可能性。
