Characterization of a family with dominant hypophosphatasia

Hu, Jan C.C.; Plaetke, Rosemary; Mornet, Étienne; Zhang, Chuhua; Sun, Xiaoling; Thomas, Huw F.; Simmer, James P.

doi:10.1034/j.1600-0722.2000.108003189.x

Cited by 81 publications

(71 citation statements)

References 5 publications

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“…To date, approximately 70 mutations in the TNSALP gene have been reported (Weiss et al 1988b;Henthorn et al 1992;Orimo et al 1994Orimo et al , 1997Ozono et al 1996;Mornet et al 1998;Goseki-Sone et al 1998;Sugimoto et al 1998;Taillandier et al 1999Taillandier et al , 2000Zurutuza et al 1999;Hu et al 2000;Mochizuki et al 2000). By using exhaustive sequencing of the gene, we identified two allelic mutations in 86% of the 62 patients tested in our laboratory and affected with various forms of the disease.…”

Section: Introductionmentioning

confidence: 79%

“…1a) were evaluated clinically and by laboratory tests at the Health Science Center of the University of Texas School of Dentistry, San Antonio (Hu et al 2000). The probands were a 6-year-old girl (IV-6) and her twin brother showing enamel hypoplasia, premature loss of fully rooted anterior teeth at age 3.5 years, and complete absence of cementum on the root surface.…”

Section: Family Amentioning

confidence: 99%

“…Dominant transmission of hypophosphatasia has been suggested on the basis of pedigree and laboratory data (Whyte et al 1979(Whyte et al , 1982Eastman and Bixler 1983;Eberic et al 1984). More recently, the mutations responsible for this condition have been described: D361 V Müller et al 2000), A99T (Hu et al 2000), and G232 V (Nunes et al 2000).…”

Section: Introductionmentioning

confidence: 97%

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A molecular approach to dominance in hypophosphatasia

et al. 2001

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Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity. The disease is highly variable in its clinical expression, because of various mutations in the TNSALP gene. In approximately 14% of the patients tested in our laboratory, only one TNSALP gene mutation was found, despite exhaustive sequencing of the gene, suggesting that missing mutations are harbored in intron or regulatory sequences or that the disease is dominantly transmitted. The distinction between these two situations is of importance, especially in terms of genetic counseling, but dominance is sometimes difficult to conclusively determine by using familial analysis since expression of the disease may be highly variable, with parents of even severely affected children showing no or extremely mild symptoms of the disease. We report here the study of eight point mutations (G46 V, A99T, S164L, R167 W, R206 W, G232 V, N461I, I473F) found in patients with no other detectable mutation. Three of these mutations, G46 V, S164L, and I473F, have not previously been described. Pedigree and/or serum alkaline phosphatase data suggested possible dominant transmission in families with A99T, R167 W, and G232 V. By means of site-directed mutagenesis, transfections in COS-1 cells, and three-dimensional (3D) modeling, we evaluated the possible dominant effect of these eight mutations. The results showed that four of these mutations (G46 V, A99T, R167 W, and N461I) exhibited a negative dominant effect by inhibiting the enzymatic activity of the heterodimer, whereas the four others did not show such inhibition. Strong inhibition resulted in severe hypophosphatasia, whereas partial inhibition resulted in milder forms of the disease. Analysis of the 3D model of the enzyme showed that mutations exhibiting a dominant effect were clustered in two regions, viz., the active site and an area probably interacting with a region having a particular biological function such as dimerization, tetramerization, or membrane anchoring.

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Section: Introductionmentioning

confidence: 79%

Section: Family Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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A molecular approach to dominance in hypophosphatasia

et al. 2001

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“…The milder forms can be transmitted as either autosomal recessive or autosomal dominant traits and are due to mutations that reduce but do not suppress enzyme activity. In heterozygotes, some severe mutations may cause mild forms of HPP because of a dominant negative effect [5,6,[25][26][27][28]. Significantly different phenotypic presentations of the disease may even occur within a family [29].…”

Section: Geneticsmentioning

confidence: 94%

Hypophosphatasia: an overview of the disease and its treatment

Bianchi

2015

Osteoporos Int

108

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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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“…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%

Conditional Alpl Ablation 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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Characterization of a family with dominant hypophosphatasia

Cited by 81 publications

References 5 publications

A molecular approach to dominance in hypophosphatasia

A molecular approach to dominance in hypophosphatasia

Hypophosphatasia: an overview of the disease and its treatment

Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia

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