Loss-of-Function ENPP1 Mutations Cause Both Generalized Arterial Calcification of Infancy and Autosomal-Recessive Hypophosphatemic Rickets

Abstract

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization.

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

“…These biochemical findings excluded rickets from nutritional deficiencies, and rapidly corrected when dairy product consumption decreased. Some GACI patients develop hypophosphatemic rickets, (18,25,70) perhaps related to the disturbance of PPi metabolism. (71) Acquired hypophosphatemia and rickets (OMIM# 613312) caused by his two altered ENPP1 alleles was an unlikely cause of his bone problems because his serum Pi level fell below the normal range just once as we followed him and without hyperphosphaturia.…”

“…However, hypophosphatemic rickets has occurred in a few surviving GACI patients at varying ages both with and without bisphosphonate treatment. (18,19,24,25) We report a 7-year-old boy with GACI and severe skeletal toxicity from protracted EHDP therapy including rickets that mimicked severe hypophosphatasia (HPP) and bone modeling abnormalities found in osteopetrosis (OPT).…”

Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets

“…5 In 2006, a mutation in the gene encoding for the dentin matrix protein (DMP1; MIM 600980) was identified in patients with autosomal recessive HR (ARHR1; MIM 241520), 6 and a mutation in ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1; MIM 173335) was in 2010 shown to cause autosomal recessive HR (ARHR2; MIM 613312). 7,8 XLHR, ADHR, ARHR1 and ARHR2 share identical biochemical characteristics of excessive renal phosphate wasting and low-serum phosphate associated with elevated levels of serum FGF23 and accompanied by inappropriately low serum 1,25-dihydroxyvitamin D (1,25(OH) 2 D). 8,9 Two types of HR differ biochemically from the four described types, as they are characterised by hypercalciuria: Hereditary HR with hypercalciuria (HHRH; MIM 241530), where the hypercalciuria is due to increased serum 1,25(OH) 2 D. The inheritance is autosomal recessive and the disease is caused by a mutation in the sodium-cotransporter gene (SLC34A3; MIM 609826), identified in 2006.…”

“…7,8 XLHR, ADHR, ARHR1 and ARHR2 share identical biochemical characteristics of excessive renal phosphate wasting and low-serum phosphate associated with elevated levels of serum FGF23 and accompanied by inappropriately low serum 1,25-dihydroxyvitamin D (1,25(OH) 2 D). 8,9 Two types of HR differ biochemically from the four described types, as they are characterised by hypercalciuria: Hereditary HR with hypercalciuria (HHRH; MIM 241530), where the hypercalciuria is due to increased serum 1,25(OH) 2 D. The inheritance is autosomal recessive and the disease is caused by a mutation in the sodium-cotransporter gene (SLC34A3; MIM 609826), identified in 2006. 10,11 The second type is X-linked recessive HR (MIM 300554), characterised by proximal renal tubulopathy and Fanconi syndrome caused by a mutation in the gene coding for the chloride channel 5 (CLCN5; MIM 300008).…”

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

“…Most importantly, this type of mutation can cause an elevation in FGF23. 22,42 It is worthwhile to mention that loss of function mutation in ENPP1 can lead to either autosomal recessive hypophosphatemia or generalized arterial calcification in infancy (GACI). 21,64 It is hard to determine the potential factors for developing either ARHR2 or GACI.…”