Ecto/nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) loss-of-function mutations cause generalized arterial calcification of infancy evolving towards hypophosphatemic rickets (PMID:24216977).
Inactivating mutations in ENPP1 have previously been described to cause generalized arterial calcification of infancy (GACI). That both GACI and hypophosphatemic rickets are caused by loss-of-function mutations is most strongly supported by the observation of a single family, in which the father has hypophosphatemic rickets whereas his son is affected by severe GACI plus hypophosphatemia, although both carry the same homozygous
ENPP1 mutation (PMID:20137773).
In a cohort of 60 probands with autosomal recessive hypophosphatemic rickets, who were negative for mutation in known hypophosphatemia genes, Lorenz-Depiereux et al. (2010) sequenced the candidate gene ENPP1 (173335) and identified homozygosity for a deletion, missense, or frameshift ...In a cohort of 60 probands with autosomal recessive hypophosphatemic rickets, who were negative for mutation in known hypophosphatemia genes, Lorenz-Depiereux et al. (2010) sequenced the candidate gene ENPP1 (173335) and identified homozygosity for a deletion, missense, or frameshift mutation in 4 families (173335.0010-173335.0012) that were not found in 355 controls. In 1 family, previously studied by Rutsch et al. (2003) ('family 4'), a father and son who were both homozygous for a missense mutation (G266V; 173335.0011) had different phenotypes: the father had hypophosphatemic rickets, whereas his son had severe generalized arterial calcification of infancy (GACI; 208000) and hypophosphatemia. Ultrasound examination of large blood vessels in the father and the other 4 mutation-positive patients showed normal carotid and renal arteries and a normal thoracic and abdominal aorta. Lorenz-Depiereux et al. (2010) found inappropriately elevated plasma FGF23 (605380) levels in all 6 patients with ENPP1 mutations and concluded that this is the fourth gene (in addition to PHEX (300550), DMP1 (600980), and FGF23 itself) that, if mutated, causes hypophosphatemic rickets due to elevated FGF23 levels. In a Bedouin family with ARHR mapping to chromosome 6q23, Levy-Litan et al. (2010) sequenced the candidate gene ENPP1 and identified homozygosity for a missense mutation (Y901S; 173335.0013) that segregated with disease and was not found in 236 Bedouin controls from the same geographic region. X-rays of the chest, abdomen, and lower limbs of the 3 affected individuals showed no evidence of vascular or periarticular calcifications