Clinical, biochemical, and pathophysiological analysis of SLC34A1 mutations

Abstract

Mutations in SLC34A1, encoding the proximal tubular sodium–phosphate transporter NaPi‐IIa, may cause a range of clinical phenotypes including infantile hypercalcemia, a proximal renal Fanconi syndrome, which are typically autosomal recessive, and hypophosphatemic nephrolithiasis, which may be an autosomal dominant trait. Here, we report two patients with mixed clinical phenotypes, both with metabolic acidosis, hyperphosphaturia, and renal stones. Patient A had a single heterozygous pathogenic missense mutation (p.I456N) in SLC34A1, consistent with the autosomal dominant pattern of renal stone disease in this family. Patient B, with an autosomal recessive pattern of disease, was compound heterozygous for SLC34A1 variants; a missense variant (p.R512C) together with a relatively common in‐frame deletion p.V91A97del7 (91del7). Xenopus oocyte and renal (HKC‐8) cell line transfection studies of the variants revealed limited cell surface localization, consistent with trafficking defects. Co‐expression of wild‐type and I456N and 91del7 appeared to cause intracellular retention in HKC‐8, whereas the R512C mutant had a less dominant effect. Expression in Xenopus oocytes failed to demonstrate a significant dominant negative effect for I456N and R512C; however, a negative impact of 91del7 on [32P]phosphate transport was found. In conclusion, we have investigated pathogenic alleles of SLC34A1 which contribute to both autosomal dominant and autosomal recessive renal stone disease.

Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

“…Many of these mutations are located within the predicted highly conserved transmembrane domains of the transporter possibly disturbing folding and/or stability of the protein in the membrane. Consistently, the functional analysis of several of these mutants demonstrated function possibly due to trafficking defects with intracellular retention of the mutant protein [88,81,19,17,23].…”

“…An in-frame deletion of 7 amino acids at the cytoplasmic N-terminal tail 91del7is of particular interest. The mutation has been detected in several patients either in compound heterozygosity or in homozygosity [88,23,38]. The clinical symptoms of homozygous and compound heterozygous patients are similar to patients carrying other SLC34A1 mutations strongly suggesting that the 91del7 mutation is fully pathogenic.…”

“…However, functional studies provide evidence for only a very mild transport defect [88,60,23] with only little reduction in apical expression consistent with a possible trafficking defect [88]. Of interest, this mutation has a high minor allele frequency of 0.018 (ExAC http://exac.broadinstitute.org/) suggesting that nearly 2 % of the general population carries this mutation on one allele.…”

“…Patients from one large family with a 21-nucleotide insertion in the transporter also showed symptoms of a more generalized proximal tubular dysfunction with unusually high calcitriol levels atypical for Fanconi-like syndromes [67,17]. In some cases, associations were present with metabolic acidosis or epilepsy, sensorineural deafness and learning deficiencies which may not be directly linked to mutations in SLC34A1 [23]. Large deletions encompassing SLC34A1 are found in patients with Sotos syndrome with learning deficiencies, facial dysmorphia, overgrowth, hypercalcemia, and nephrocalcinosis [47].…”

Renal tubular acidosis in pediatrics: A review article

“…Both homozygous and heterozygous SLC4A1 mutations and hemoglobinopathy [AMJ 2019;12(2):63-70] affects the morphology of red cells and the degree of haemolytic anaemia, which is worsen by acidosis. 14 18 Fanconi-Bickel syndrome missense mutation in SLC2A2, 19 is a rare autosomal recessive disease caused by a deficiency of glucose transporter 2 (GLUT2), a member of the facilitative glucose transporter family. 20 The most common type is cystinosis caused by CTNS mutation and is a lysosomal storage disorder.…”