Hypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and, dentin matrix protein-1 (DMP1) and ecto-nucleotide pyro phosphatase/phosphodiesterase 1 (ENPP1) genes, respectively. Mutations in these genes are believed to cause elevation of circulating FGF23 protein. Increase in FGF23 disrupts phosphate homeostasis, leading to HR. This review aims to summarize phosphate homeostasis and focuses on the genes and mutations related to XLH, ADHR, and ARHR. A compilation of XLH mutation hotspots based on the PHEX gene database and mutations found in the FGF23, DMP1, and ENPP1 genes are also made available in this review.

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Chronic relapsing inflammatory bowel disease is strongly linked to an increased risk of colitis-associated cancer (CAC). One of the well-known inflammatory carcinogenesis pathways, phosphatidylinositol 3-kinase (PI3K), was identified to be a crucial mechanism in long-standing ulcerative colitis (UC). The goal of this study was to identify somatic variants in the cytokine-induced PI3K-related genes in UC, colorectal cancer (CRC) and CAC. Thirty biopsies (n = 8 long-standing UC, n = 11 CRC, n = 8 paired normal colorectal mucosa and n = 3 CAC) were subjected to targeted sequencing on 13 PI3K-related genes using Illumina sequencing and the SureSelectXT Target Enrichment System. The Genome Analysis Toolkit was used to analyze variants, while ANNOVAR was employed to detect annotations. There were 5116 intronic, 355 exonic, 172 untranslated region (UTR) and 59 noncoding intronic variations detected across all samples. Apart from a very small number of frameshifts, the distribution of missense and synonymous variants was almost equal. We discovered changed levels of IL23R, IL12Rß1, IL12Rß2, TYK2, JAK2 and OSMR in more than 50% of the samples. The IL23R variant in the UTR region, rs10889677, was identified to be a possible variant that might potentially connect CAC with UC and CRC. Additional secondary structure prediction using RNAfold revealed that mutant structures were more unstable than wildtype structures. Further functional research on the potential variants is, therefore, highly recommended since it may provide insight on the relationship between inflammation and cancer risk in the cytokine-induced PI3K pathway.

Hypophosphataemic Rickets (HR) is a rare bone disorder characterised by chronic hypophosphataemia caused by defective phosphate reabsorption in the renal tubules. Variants in phosphate-regulating endopeptidase homolog, X-linked (PHEX), fibroblast growth factor-23 (FGF23) and dentin matrix protein-1 (DMP1) genes contribute to X-linked dominant, autosomal dominant and autosomal recessive forms of HR, respectively. In this study, four Malaysian patients’ DNA samples were subjected to polymerase chain reaction and Sanger sequencing to identify the types and locations of the variants. Then, in silico study was conducted based on the variants found to predict the effects of amino acid substitution on protein functions using SIFT and PolyPhen-2 software and RNAfold was used to construct the mRNA secondary structure. Mutational analyses had revealed two variants in PHEX; c.10G>C (E4Q), c.1970A>G (Y657C), one mutation in FGF23; c.716C>T (T239M) and three variants on DMP1; c.309A>T (S69C), c.1322C>T (S406S), c.1334G>A (E410E). The variants in these Malay patients were previously reported in different ethnic HR patients. Protein prediction programs suggested that the PHEX Y657C and DMP1 S69C variants may affect protein function. All variants were predicted to alter the secondary mRNA structure. These findings suggest that these missense and silent variants may lead to changes in protein function and mRNA secondary structure that are associated with the manifestation of HR phenotype.

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