Clinical heterogeneity and phenotypic expansion of napi-iia-associated disease

Korcan Demir, Melek Yildiz, Hilla Bahat, Michael Goldman, Nisreen Hassan, Shay Tzur, Ayala Ofir, Daniella Magen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Context: 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. Objectives: We studied the molecular basis of idiopathic infantile hypercalcemia with partial proximal tubulopathy in two apparently unrelated patients of Israeli and Turkish descent. Design: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)4604-4614
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Issue number12
StatePublished - 2017
Externally publishedYes


FundersFunder number
Rappaport Research Institute
Technion–Israel Institute of Technology, Haifa, Israel


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