Autosomal-Recessive Hypophosphatemic Rickets Is Associated with an Inactivation Mutation in the ENPP1 Gene

Levy-Litan, Varda; Hershkovitz, Eli; Avizov, Luba; Leventhal, Neta; Bercovich, Dani; Chalifa‐Caspi, Vered; Manor, Esther; Buriakovsky, Sophia; Hadad, Yair; Goding, James W.; Parvari, Ruti

doi:10.1016/j.ajhg.2010.01.010

Cited by 265 publications

(180 citation statements)

References 23 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Otero

Gottesman

McAlister

et al. 2012

Journal of Bone and Mineral Research

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Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of GACI patients die by 6 months of age from cardiac ischemia and congestive heart failure. The first-generation bisphosphonate etidronate (EHDP; ethane-1-hydroxy-1,1-diphosphonic acid, also known as 1-hydroxyethylidene-bisphosphonate) inhibits bone resorption and can mimic endogenous inorganic pyrophosphate by blocking mineralization. With EHDP therapy for GACI, AC may resolve without recurrence upon treatment cessation. Skeletal disease is not an early characteristic of GACI, but rickets can appear from acquired hypophosphatemia or prolonged EHDP therapy. We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC was gone after 5 months of EHDP therapy during infancy, but GACI-related joint calcifications progressed. He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal. Serum osteocalcin was low and the brain isoform of creatine kinase and tartrate-resistant acid phosphatase 5b (TRAP-5b) were elevated as in osteopetrosis. Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, long-bone bowing, widened physes, as well as metaphyseal osteosclerosis, cupping and fraying, and ''tongues'' of radiolucency. Radiographic features of osteopetrosis included osteosclerosis and femoral Erlenmeyer flask deformity. After stopping EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in GACI from protracted EHDP therapy. Although EHDP treatment is lifesaving in GACI, surveillance for toxicity is crucial. ß

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Section: Discussionmentioning

confidence: 99%

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

Otero

Gottesman

McAlister

et al. 2012

Journal of Bone and Mineral Research

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“…5 A and B). Among these, the R456Q, L579F, L611V, C726R, N792S, E893X, and Y901S mutations abolished the enzymatic activity in human Enpp1 (5,32). The structure of mouse Enpp1 revealed that most of these residues participate in intradomain or interdomain interactions (Fig.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signaling

Kato

Nishimasu

Okudaira

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

120

162

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Enpp1 is a membrane-bound glycoprotein that regulates bone mineralization by hydrolyzing extracellular nucleotide triphosphates to produce pyrophosphate. Enpp1 dysfunction causes human diseases characterized by ectopic calcification. Enpp1 also inhibits insulin signaling, and an Enpp1 polymorphism is associated with insulin resistance. However, the precise mechanism by which Enpp1 functions in these cellular processes remains elusive. Here, we report the crystal structures of the extracellular region of mouse Enpp1 in complex with four different nucleotide monophosphates, at resolutions of 2.7-3.2 Å. The nucleotides are accommodated in a pocket formed by an insertion loop in the catalytic domain, explaining the preference of Enpp1 for an ATP substrate. Structural mapping of disease-associated mutations indicated the functional importance of the interdomain interactions. A structural comparison of Enpp1 with Enpp2, a lysophospholipase D, revealed marked differences in the domain arrangements and active-site architectures. Notably, the Enpp1 mutant lacking the insertion loop lost the nucleotide-hydrolyzing activity but instead gained the lysophospholipid-hydrolyzing activity of Enpp2. Our findings provide structural insights into how the Enpp family proteins evolved to exert their diverse cellular functions. molecular evolution | X-ray crystallography

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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This study aimed to identify the underlying genetic mutation in patients with hypophosphatemic rickets (HR). Genomic DNA was analysed for mutations in PHEX, FGF23 and CLCN5 by polymerase chain reaction (PCR) followed by denaturing highperformance liquid chromatography (dHPLC). Bi-directional sequencing was performed in samples with deviating chromatographic profiles. DMP1 and SLC34A3 were sequenced, only. In addition, a multiplex ligation-dependent probe amplification (MLPA) analysis was performed to detect larger deletions/duplications in PHEX or FGF23. Familial cases accounted for 12 probands while 12 cases were sporadic. In 20 probands, mutations were detected in PHEX of which 12 were novel, and one novel frameshift mutation was found in DMP1. Three PHEX mutations were identified by the MLPA analysis only; that is, two large deletions and one duplication. No mutations were identified in FGF23, SLC34A3 or CLCN5. By the methods used, a disease causing mutation was identified in 83% of the familial and 92% of the sporadic cases, thereby in 88% of the tested probands. Genetic analysis performed in HR patients by PCR, dHPLC, sequencing and in addition by MLPA analysis revealed a high identification rate of gene mutations causing HR, including 12 novel PHEX and one novel DMP1 mutation.

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Autosomal-Recessive Hypophosphatemic Rickets Is Associated with an Inactivation Mutation in the ENPP1 Gene

Cited by 265 publications

References 23 publications

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

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

Crystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signaling

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

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