Exome Sequencing Identifies a Novel Homozygous Mutation in the Phosphate Transporter SLC34A1 in Hypophosphatemia and Nephrocalcinosis

Rajagopal, Abbhirami; Braslavsky, Débora; Lu, James T.; Kleppe, Soledad; Clément, Florencia; Cassinelli, Hamilton; Liu, David S.; Liern, José Miguel; Vallejo, Graciela; Bergadá, Ignacio; Gibbs, Richard A.; Campeau, Philippe M.; Lee, Brendan

doi:10.1210/jc.2014-1517

Cited by 41 publications

(40 citation statements)

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“…Rajagopal et al reported another mutation in SLC34A1, p.Arg495His, in two siblings who presented with hypercalciuria and nephrocalcinosis [10].…”

Section: Discussionmentioning

confidence: 99%

“…It has remained unclear whether human heterozygous mutations may be the cause of kidney stones [7,8]. The clinical findings in the first reported homozygous NaPiIIa mutation in human included Fanconi syndrome and bone disease without hypercalciuria or nephroalcinosis [9], while another paper described hypercalcemia and nephrocalcinosis without skeletal dysfunction [10]. Recent publications strengthen the involvement of SLC34A1 in hypercalcemia and kidney stones.…”

Section: Introductionmentioning

confidence: 99%

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Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

et al. 2016

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BACKGROUND Inherited metabolic disorders associated with nephrocalcinosis are rare conditions. The aim of this study was to identify the genetic cause of an Israeli-Arab boy from a consanguineous family with severe nephrocalcinosis and kidney insufficiency. METHODS Clinical and biochemical data of the proband and family members were obtained from both previous and recent medical charts. Genomic DNA was isolated from peripheral blood cells. The coding sequence and splice sites of candidate genes (CYP24A1, CYP27B1, FGF23, KLOTHO, SLC34A3 and SLC34A1) were sequenced directly. Functional studies were performed in Xenopus laevis oocytes and in transfected opossum kidney (OK) cells. RE-SULTS Our patient was identified as having nephrocalcinosis in utero, and at the age of 16.5 years, he had kidney insufficiency but no bone disease. Genetic analysis revealed a novel homozygous missense mutation, Arg215Gln, in SLC34A1, which encodes the renal sodium phosphate cotransporter NaPiIIa. Functional studies of the Arg215Gln mutant revealed reduced transport activity in Xenopus laevis oocytes and increased intracellular cytoplasmic accumulation in OK cells. CONCLUSIONS Our findings show that dysfunction of the human NaPiIIa causes severe renal calcification that may eventually lead to reduced kidney function, rather than complications of phosphate loss.

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“…Rajagopal et al reported another mutation in SLC34A1, p.Arg495His, in two siblings who presented with hypercalciuria and nephrocalcinosis [10].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

et al. 2016

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“…Magen et al 41 reported a clinical case of autosomal recessive hypophosphatemic rickets with renal Fanconi's Syndrome secondary to an Npt2a loss-of-function genetic mutation. Likewise, Rajagopal et al 42 and Kenny et al 43 both reported case studies of mutations in the Npt2a gene that resulted in phenotypes of renal phosphate wasting with resultant hypercalcemia, hypercalciuria, and hypophosphatemia. While these clinical reports suggest that the contribution of specific renal phosphate transporters to overall phosphate homeostasis may be more nuanced than previously recognized, they provide evidence and support for Npt2a as an important determinant of serum phosphorus, as well as a critical target of regulators of renal phosphate reabsorption.…”

Section: -mentioning

confidence: 99%

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

Murray¹

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PTH is a critical regulator of serum phosphorus. We have previously shown that PTH decreases proximal tubule NpT2a mRNA expression through post‐transcriptional mechanisms, and that this effect can be reproduced by treatment with 8‐bromo‐cAMP, a PKA activator, but not phorbol myristate acetate, a PKC activator. We hypothesize that PKA is the primary mediator of NpT2a mRNA destabilization by PTH. To determine the contribution of each pathway to the PTH response, opossum kidney (OK) cells were treated with selective protein kinase inhibitors in the presence of PTH, and NpT2a mRNA expression was measured by qRT‐PCR. Pretreatment with 10µM PKC inhibitor peptide (PKCi) followed by 100nM PTH for 6h produced a 43.9% decrease in NpT2a mRNA versus PKCi alone. Pretreatment with 10µM H‐89, a PKA inhibitor, prevented the initial decrease in NpT2a mRNA by PTH but did not prevent the ultimate reduction. 8CPT‐2Me‐cAMP, a selective activator of Epac, failed to produce a decrease in NpT2a mRNA after 6h. We conclude that the initial effect of PTH on NpT2a mRNA is PKA‐dependent, whereas chronic regulation involves both the PKA and PKC pathways. Grant Funding Source: Support for this project is provided by VA to EDL.

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“…ClC5, FcRn, NaPi-IIa gene are related with metabolic renal disease. DAB2, GIPC has an uncertain meaning in human pathology, but their pathogenic effect must be explored [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].Considering the interaction between these genes, it would be very useful to analyze the relationship between polymorphisms of single base changes (SNP) of these genes, or the blocks of haplotypes and haplogroups that can be constructed with sets of SNP in T2D patients. Specially, the relationship of such variants with the development of peripheral neuropathy and the appropriate metformin doses.…”

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confidence: 99%

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confidence: 99%

Exploration of gene variations in the transcytosis system as a policy proposal for the personalized therapy in type 2 diabetes mellitus

Flores-Alvarado¹,

Villafán-Bernal²,

Cabrera-Pivaral³

et al. 2017

J Med Therap

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The gene system of transcytosis, integrated by LRP2, AMN, CUBN, ARH, AMN and CUBN, might be important for the treatment and monitoring of chronic complications of diabetics, as well as for drug interactions, since they mediate the reuptake of vitamins such as B complex, folic acid and lipoproteins, which are closely related to the progression of diabetes. That is why polymorphisms in those genes could be targets of personalized medicine, to improve the quality of health care. It is important for both the clinical researcher and physician to explore new personalized treatment options for better care of the diabetic patient. The search for genetic or genomic markers in order to predict complications of disease, progression as well as to evaluate the therapeutic response to drugs and the presentation of adverse effects is an area to be explored, considering the high costs that represent the attention of diabetics to hospitals from the public sector. Other reasons are that type 2 diabetes mellitus (T2D) patients develop complications related with the progression of the disease, as well as, adverse and side effects resulting from drug interactions [1,2]. T2D commonly presents deficiency of vitamin B complex, associated with the long-term consumption of metformin. The consequences of this deficiency are increased cardiovascular risk, renal damage and higher risk of peripheral neuropathy and senile dementia [1,2]. Additionally, the chronic consumption of statins for the control of hypercholesterolemia and cardiovascular risk results in secondary dyslipidemia myocytes inflammation [1,2].The common element that might explain the previously described complications and side effects in T2D diabetic patients is an axis of genes that encode for the system of transcytosis in the cellular membranes from small intestine, kidney, liver, striated muscle, and other tissues. The components of this transcytosis system are LRP2, AMN, CUBN, ARH, Dab2, GIPC, NHE3, ClC5, FcRn and NaPi-IIa, which mediate the reuptake of B complex vitamins, including folic acid among other molecules [3][4][5][6][7][8][9][10].The clinical effect of these genes might be seen in the development of different diseases or clinical conditions (Table 1). Mutations in LRP2 have been associated with diabetes, aminoglucosides response, DonnaiBarrow syndrome (DBS), Facio-oculo-acoustic-renal syndrome (FOAR) and Alzheimer's disease. While mutations in AMN and CUB occur with megaloblastic anemia plus albuminuria. CUBallelic variants are related to the progression of renal damage and ARH variations are associated with hypercholesterolemia [3][4][5][6][7][8][9][10]. NHE3 mutations show association with congenital sodium diarrhea, whereas ClC5 gene is related to renal failure or Dent disease. ClC5, FcRn, NaPi-IIa gene are related with metabolic renal disease. DAB2, GIPC has an uncertain meaning in human pathology, but their pathogenic effect must be explored [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].Considering the interaction between these genes...

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Exome Sequencing Identifies a Novel Homozygous Mutation in the Phosphate Transporter SLC34A1 in Hypophosphatemia and Nephrocalcinosis

Cited by 41 publications

References 20 publications

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

Exploration of gene variations in the transcytosis system as a policy proposal for the personalized therapy in type 2 diabetes mellitus

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