Plasma P increased somewhat in S2* but little change was seen in S5*. Problems with treatment compliance were acknowledged and the therapy was subsequently terminated. Candidate gene analysis

of the SLC34AC gene, encoding a type IIc Cyclopamine sodium-phosphate transporter (NaPi-IIc) expressed in the kidney, was conducted in the DNA sample from the youngest affected sibling (S1*) (Fig. 1). Three SNPs were found for which the other family members were then screened. Two of the SNPs had been previously reported on the NCBI database and had been assigned the following reference numbers rs28542318 and rs74842953. These SNPs referred to a non-synonymous mutation E513V (c.1538A > T) and a synonymous mutation L599L (c.1795 T > C) respectively. In silico mutation analysis suggested that these two SNPs were benign polymorphisms and they were unique to S1* and were not present in the other investigated family members. The third SNP was a novel non-synonymous mutation resulting in an amino acid change S168F (c.503C > T). Blast alignment results indicated that the flanking amino acid regions at the site of the S168F mutation were highly conserved throughout species

( Table 3). In silico mutation analysis predicted that this SNP would cause a damaging RO4929097 solubility dmso mutation in the NaPi-IIc protein, the likely cause being the loss of function of the transmembrane domain spanning 133–188 amino acids. Prediction analysis, suggested that the protein product containing S168F was of normal length (599 amino acids) and that the correct reading frame was maintained. The S168F mutation was present homozygously in the affected siblings (S5*, S2* and S1*) and heterozygously in the unaffected family members ( Fig. 1). The Republic of The Gambia (latitude 13°N) in Adenosine West Africa has a hot and dry tropical climate with a single wet season from June to October. There is abundant UVB-containing sunshine throughout the year and a lifestyle that does not limit skin UVB-exposure. Cases of rickets have, however, been reported and have been attributed predominantly

to a chronically low dietary calcium (Ca) intake leading to a 1,25(OH)2D-driven increase in FGF23 leading to urinary phosphate (P) wasting and rickets [1] and [2]. The family described in this study is, however, strikingly different to our previous reports of rickets in The Gambia. To our knowledge, this study documents the first cases of hereditary hypophosphataemic rickets with hypercalciuria (HHRH) in Africa. The cause of HHRH is a mutation within the gene encoding the Type IIc sodium-phosphate co-transporter [3] and [4]. There are two major NaPi co-transporters involved in P reabsorption in the proximal tubule of the kidney. These are NaPi-Type IIa and -Type IIc, both of which are regulated by FGF23 and PTH.