ORPHA: 289176; DO: 0050949;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q23.2 | Hypophosphatemic rickets, autosomal recessive, 2 | 613312 | Autosomal recessive | 3 | ENPP1 | 173335 |
A number sign (#) is used with this entry because of evidence that autosomal recessive hypophosphatemic rickets-2 (ARHR2) is caused by homozygous mutation in the ENPP1 gene (173335) on chromosome 6q23.
Mutation in ENPP1 also causes generalized arterial calcification of infancy (GACI; 208000).
For a general phenotypic description and a discussion of genetic heterogeneity of hypophosphatemic rickets, see 193100.
Lorenz-Depiereux et al. (2010) performed genomewide linkage analysis in 2 families segregating autosomal recessive hypophosphatemic rickets (ARHR) and then analyzed the data by homozygosity mapping, which revealed a 4.1-Mb candidate region on chromosome 6q23 between rs9388766 and rs6569926, an interval containing approximately 35 genes.
In a Bedouin family with ARHR, Levy-Litan et al. (2010) performed homozygosity mapping and identified linkage to chromosome 6q23, obtaining a lod score of 3.45 for D6S262 under an assumption of recessive inheritance with 99% penetrance and an incidence of 0.01 or 0.001 of the disease allele in the population. Multipoint analysis yielded a lod score of 4.27 for a 7.39-Mb linkage interval containing 70 genes.
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.
Levy-Litan, V., Hershkovitz, E., Avizov, L., Leventhal, N., Bercovich, D., Chalifa-Caspi, V., Manor, E., Buriakovsky, S., Hadad, Y., Goding, J., Parvari, R. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am. J. Hum. Genet. 86: 273-278, 2010. [PubMed: 20137772] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.010]
Lorenz-Depiereux, B., Schnabel, D., Tiosano, D., Hausler, G., Strom, T. M. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am. J. Hum. Genet. 86: 267-272, 2010. [PubMed: 20137773] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.006]
Rutsch, F., Ruf, N., Vaingankar, S., Toliat, M. R., Suk, A., Hohne, W., Schauer, G., Lehmann, M., Roscioli, T., Schnabel, D., Epplen, J. T., Knisely, A., and 10 others. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nature Genet. 34: 379-381, 2003. [PubMed: 12881724] [Full Text: https://doi.org/10.1038/ng1221]