Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia

Silvent, Jérémie; Gasse, Barbara; Mornet, Étienne; Sire, Jean‐Yves

doi:10.1074/jbc.m114.576843

Cited by 53 publications

(65 citation statements)

References 46 publications

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“…The inheritance mechanism can be autosomal recessive or dominant. About 80 % of the known mutations are missense point mutations, 10 % are small deletions, 4 % splicing mutations, 3 % nonsense mutations, 2 % small insertions, and ≤1 % complex insertion/deletions, large deletions, or mutations in the regulatory sequence [21,23,24].…”

Section: Geneticsmentioning

confidence: 99%

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Hypophosphatasia: an overview of the disease and its treatment

Bianchi

2015

Osteoporos Int

105

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This review presents the current knowledge on hypophosphatasia, a rare genetic disease of very variable severity (from lethal to mild) and clinical presentation, caused by defective production of tissue-non-specific alkaline phosphatase (TNSALP). Hypophosphatasia can affect babies in utero as well as infants, children, and adults. The article first presents the genetics of TNSALP and its many known mutations underlying the disease. Then, it presents the epidemiology, classification, and clinical presentation of the six different forms of the disease (perinatal lethal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia) as well as the essential diagnostic clues. The last section on treatment presents a survey of the therapeutic approaches, up to the ongoing phase 2 studies of enzyme replacement therapy.

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Section: Geneticsmentioning

confidence: 99%

“…The ALPL gene consists of 12 exons distributed over 50 kilobases [19,20]. Human TNSALP is a chain of 524 amino acid residues [21]. The genes of the other, tissue-specific, ALP isoenzymes are located on the long arm of chromosome 2 (2q34-37) [22].…”

Section: Geneticsmentioning

confidence: 99%

Hypophosphatasia: an overview of the disease and its treatment

Bianchi

2015

Osteoporos Int

105

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“…However, early lethality of these mice limits analyses to developmental stages, precluding longer-term studies on tooth function, dentoalveolar remodeling, repair, and regeneration. One approach to resolve this limitation was creation of a knock-in mouse harboring a dominant-negative human ALPL mutation associated with odontohypophosphatasia (Hu et al 2000;Silvent et al 2014). Alpl +/A116T mice featured 50% reduced plasma ALP and no apparent skeletal defects, and they lived to be >1 y old .…”

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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“…Genotype-phenotype correlation studies have demonstrated that loss-of-function variants typically cause severe forms, while missense changes often result in milder forms. The protein product of ALPL is tissue nonspecific (liver/bone/ kidney) alkaline phosphatase, an enzyme that is essential for calcium and phosphorus mineralization in developing bones and teeth [Silvent et al, 2014].…”

Section: Molecular Findingsmentioning

confidence: 99%

Beyond osteogenesis imperfecta: Causes of fractures during infancy and childhood

Bronicki¹,

Stevenson²,

Spranger³

2015

American J of Med Genetics Pt C

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Fractures in infancy or early childhood require prompt evaluation with consideration of accidental or non-accidental trauma as well as a large number of genetic disorders that predispose to fractures. Bone fragility has been reported in more than 100 genetic disorders, including skeletal dysplasias, inborn errors of metabolism and congenital insensitivity to pain. Most of these disorders are rare but often have distinctive clinical or radiographic findings to assist in the diagnosis. Gene sequencing is available, albeit connective tissue and skeletal dysplasia panels and biochemical studies are only helpful in a minority of cases. This article presents the clinical, radiographic, and molecular profiles of the most common heritable disorders other than osteogenesis imperfecta with increased bone fragility. In addition, the clinicians must consider non-heritable influences such as extreme prematurity, prenatal viral infection and neoplasia in the diagnostic process.

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Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia

Cited by 53 publications

References 46 publications

Hypophosphatasia: an overview of the disease and its treatment

Hypophosphatasia: an overview of the disease and its treatment

ConditionalAlplAblation Phenocopies Dental Defects of Hypophosphatasia

Beyond osteogenesis imperfecta: Causes of fractures during infancy and childhood

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