A novel point mutation (C571T) in the tissue‐non‐specific alkaline phosphatase gene in a case of adult‐type hypophosphatasia

Watanabe, Hisashi; Hashimoto-Uoshima, Mariko; Goseki‐Sone, Masae; Orimo, Hideo; Ishikawa, Isao

doi:10.1034/j.1601-0825.2001.00740.x

Cited by 17 publications

(8 citation statements)

References 24 publications

(26 reference statements)

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“…So the kinetic properties of the D361V mutant and the fact that it forms heterodimers can explain its role in causing dominantly inherited hypophosphatasia. The same explanation may hold true for the A115V mutation, which was reported as dominant and found in a patient with adult hypophosphatasia (28) …”

Section: Discussionmentioning

confidence: 62%

“…The same explanation may hold true for the A115V mutation, which was reported as dominant and found in a patient with adult hypophosphatasia. (28) One mutant (A160T) (29) had an increased k cat when measured with pNPP at pH 9.8 and with PLP, but not when measured with PPi and pNPP at pH 7.5. In fact, an increase in K m was observed for both PLP and pNPP under these conditions.…”

Section: Mauro Et Almentioning

confidence: 97%

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Kinetic Characterization of Hypophosphatasia Mutations With Physiological Substrates

Mauro

Manes

Hessle

et al. 2002

Journal of Bone and Mineral Research

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We have analyzed 16 missense mutations of the tissue-nonspecific AP (TNAP) gene found in patients with hypophosphatasia. These mutations span the phenotypic spectrum of the disease, from the lethal perinatal/ infantile forms to the less severe adult and odontohypophosphatasia. Site-directed mutagenesis was used to introduce a sequence tag into the TNAP cDNA and eliminate the glycosylphosphatidylinositol (GPI)-anchor recognition sequence to produce a secreted epitope-tagged TNAP (setTNAP). The properties of GPI-anchored TNAP (gpiTNAP) and setTNAP were found comparable. After introducing each single hypophosphatasia mutation, the setTNAP and mutant TNAP cDNAs were expressed in COS-1 cells and the recombinant flagged enzymes were affinity purified. We characterized the kinetic behavior, inhibition, and heat stability properties of each mutant using the artificial substrate p-nitrophenylphosphate (pNPP) at pH 9.8. We also determined the ability of the mutants to metabolize two natural substrates of TNAP, that is, pyridoxal-5-phosphate (PLP) and inorganic pyrophosphate (PPi), at physiological pH. Six of the mutant enzymes were completely devoid of catalytic activity (R54C, R54P, A94T, R206W, G317D, and V365I), and 10 others (A16V, A115V, A160T, A162T, E174K, E174G, D277A, E281K, D361V, and G439R) showed various levels of residual activity. The A160T substitution was found to decrease the catalytic efficiency of the mutant enzyme toward pNPP to retain normal activity toward PPi and to display increased activity toward PLP. The A162T substitution caused a considerable reduction in the pNPPase, PPiase, and PLPase activities of the mutant enzyme. The D277A mutant was found to maintain high catalytic efficiency toward pNPP as substrate but not against PLP or PPi. Three mutations ( E174G, E174K, and E281K) were found to retain normal or slightly subnormal catalytic efficiency toward pNPP and PPi but not against PLP. Because abnormalities in PLP metabolism have been shown to cause epileptic seizures in mice null for the TNAP gene, these kinetic data help explain the variable expressivity of epileptic seizures in hypophosphatasia patients. (J Bone Miner Res 2002;17:1383-1391)

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Section: Discussionmentioning

confidence: 62%

Section: Mauro Et Almentioning

confidence: 97%

Kinetic Characterization of Hypophosphatasia Mutations With Physiological Substrates

Mauro

Manes

Hessle

et al. 2002

Journal of Bone and Mineral Research

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“…For instance, the intrafamiliar occurrence of Papillon–Lefevre syndrome was described decades ago (64), and data about the precise role of genetic factors in the pathogenesis of this disease and its periodontal component are now emerging (245). Severe periodontal manifestations in other heritable syndromes have also been established (239, 241).…”

Section: Risk Factors and Risk Indicators For Periodontal Diseasesmentioning

confidence: 99%

Global risk factors and risk indicators for periodontal diseases

Albandar¹

2002

Periodontology 2000

468

469

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“…While we did not analyze the presence of microbial infections, we noted no severe infiltration of neutrophils into the periodontia of either cKO model (data not shown). Periodontal disease has been reported in some HPP patients (Bloch-Zupan 2016;Foster, Ramnitz, et al 2014;Rodrigues et al 2012;Watanabe et al 2001), although prevalence and etiology are not well described. The Alpl +/A116T mouse model also showed increased osteoclast numbers in alveolar bone, though periodontal function was maintained and alveolar bone loss not detected .…”

Section: Dental Defects In Mouse Models Of Late-onset Hppmentioning

confidence: 99%

ConditionalAlplAblation Phenocopies Dental Defects of Hypophosphatasia

et al. 2016

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Loss-of-function mutations in ALPL result in hypophosphatasia (HPP), an inborn error of metabolism that causes defective skeletal and dental mineralization. ALPL encodes tissue-nonspecific alkaline phosphatase, an enzyme expressed in bone, teeth, liver, and kidney that hydrolyzes the mineralization inhibitor inorganic pyrophosphate. As Alpl-null mice die before weaning, we aimed to generate mouse models of late-onset HPP with extended life spans by engineering a floxed Alpl allele, allowing for conditional gene ablation (conditional knockout [cKO]) when crossed with Cre recombinase transgenic mice. The authors hypothesized that targeted deletion of Alpl in osteoblasts and selected dental cells (Col1a1-cKO) or deletion in chondrocytes, osteoblasts, and craniofacial mesenchyme (Prx1-cKO) would phenocopy skeletal and dental manifestations of late-onset HPP. Col1a1-cKO and Prx1-cKO mice were viable and fertile, and they did not manifest the epileptic seizures characteristic of the Alpl-/- model of severe infantile HPP. Both cKO models featured normal postnatal body weight but significant reduction as compared with wild type mice by 8 to 12 wk. Plasma alkaline phosphatase for both cKO models at 24 wk was reduced by approximately 75% as compared with controls. Radiography revealed profound skeletal defects in cKO mice, including rachitic changes, hypomineralized long bones, deformations, and signs of fractures. Microcomputed tomography confirmed quantitative differences in cortical and trabecular bone, including decreased cortical thickness and mineral density. Col1a1-cKO mice exhibited classic signs of HPP dentoalveolar disease, including short molar roots with thin dentin, lack of acellular cementum, and osteoid accumulation in alveolar bone. Prx1-cKO mice exhibited the same array of periodontal defects but featured less affected molar dentin. Both cKO models exhibited reduced alveolar bone height and 4-fold increased numbers of osteoclast-like cells versus wild type at 24 wk, consistent with HPP-associated periodontal disease. These novel models of late-onset HPP can inform on long-term skeletal and dental manifestations and will provide essential tools to further studies of etiopathologies and therapeutic interventions.

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A novel point mutation (C571T) in the tissue‐non‐specific alkaline phosphatase gene in a case of adult‐type hypophosphatasia

Abstract: The C571T mutation is a new missense point mutation and appears to cause significant changes in the structure and function of TNSALP because Ala-115 is highly conserved in rat TNSALP and human tissue-non-specific, intestinal and placental ALPs.

Cited by 17 publications

References 24 publications

Kinetic Characterization of Hypophosphatasia Mutations With Physiological Substrates

Kinetic Characterization of Hypophosphatasia Mutations With Physiological Substrates

Global risk factors and risk indicators for periodontal diseases

ConditionalAlplAblation Phenocopies Dental Defects of Hypophosphatasia

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