Mutation update: Variants of the ENPP1 gene in pathologic calcification, hypophosphatemic rickets, and cutaneous hypopigmentation with punctate keratoderma

Abstract

ENPP1 encodes ENPP1, an ectonucleotidase catalyzing hydrolysis of ATP to AMP and inorganic pyrophosphate (PPi), and an endogenous plasma protein physiologically preventing ectopic calcification of connective tissues. Mutations in ENPP1 have been reported in association with a range of human genetic diseases. In this mutation update, we provide a comprehensive review of all the pathogenic variants, likely pathogenic variants, and variants of unknown significance in ENPP1 associated with three autosomal recessive disorders—generalized arterial calcification of infancy (GACI), autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and pseudoxanthoma elasticum (PXE), as well as with a predominantly autosomal dominant disorder—Cole disease. The classification of all variants is determined using the latest ACMG guidelines. A total of 140 ENPP1 variants were curated consisting of 133 previously reported variants and seven novel variants, with missense variants being the most prevalent (70.0%, 98/140). While the pathogenic variants are widely distributed in the ENPP1 gene of patientsgen without apparent genotype–phenotype correlation, eight out of nine variants associated with Cole disease are confined to the somatomedin‐B‐like (SMB) domains critical for homo‐dimerization of the ENPP1 protein.

Case Report and Review of Literature: Autosomal Recessive Hypophosphatemic Rickets Type 2 Caused by a Pathogenic Variant in ENPP1 Gene

“…Enhanced FGF23-mediated renal phosphate loss reduces bone mineralization, resulting in hypophosphatemic rickets. Thus far, a total of 140 pathogenic variants of ENPP1 have been reported in the previous peerreviewed literature (15,16), and the Human Gene Mutation Database (HGMD Professional; http://www.hgmd.cf.ac.uk/ac/ index.ph, access date: September 13, 2021). Among them, 42 variants are associated with rickets.…”

Significance of Premature Vertebral Mineralization in Zebrafish Models in Mechanistic and Pharmaceutical Research on Hereditary Multisystem Diseases

“…Pseudoxanthoma elasticum (PXE; OMIM# 264800) is an autosomal recessive metabolic disease caused by loss-of-function pathogenic variants in the ABCC6 (ATP-binding cassette, subfamily C, member 6) gene and-to a much lesser extent-the ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene [47,48]. In humans, ABCC6 encodes an ATPdependent ABC transporter, ABCC6, which is mainly present in the liver and kidneys [49].…”

Osteocytes and the pathogenesis of hypophosphatemic rickets

“…ARHR2 is caused by inactivating mutations in the ectonucleotide pyrophosphatase phosphodiesterase-1 ( ENPP1 ) gene, which encodes an ectoenzyme that catalyzes the hydrolysis of ATP to AMP and inorganic pyrophosphate (PPi) ( 58 – 60 ). PPi inhibits mineralization, and inactivating mutations in ENPP1 cause disorders characterized by ectopic calcification, such as generalized arterial calcification of infancy ( 60 , 61 ). ENPP1 is expressed in many tissues, and is highly expressed in chondrocytes, osteoblasts, and vascular smooth muscle cells ( 62 ).…”