Function of Mutant (G1144A) Tissue-Nonspecific ALP Gene From Hypophosphatasia

Watanabe, Hisashi; Goseki‐Sone, Masae; Orimo, Hideo; Hamatani, Ryoko; Takinami, Hiroyuki; Ishikawa, Isao

doi:10.1359/jbmr.2002.17.11.1945

Cited by 16 publications

(8 citation statements)

References 24 publications

(32 reference statements)

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“…Various mutations in the TNSALP gene discovered with HOPS have been analyzed (9,10,12,14,16,17,37,39) . The deletion of T at nucleotide 1559 (1559delT) seems to be a mutational hot spot in Japanese HOPS patients (9,15,40) .…”

Section: Discussionmentioning

confidence: 99%

“…HOPS is an inherited disorder characterized by a defect in skeletal mineralization caused by TNSALP deficiency. We have analyzed various mutations in the TNSALP gene (7–17) and have shown that deletion of T at a position (1559delT) located in exon 12 causes the loss of ALP activity and results in the synthesis of an abnormal TNSALP molecule, which is not expressed on the plasma membrane (9) . Clinical symptoms vary greatly among the four different subforms of the disease (perinatal, infantile, childhood, and adult), which are distinguished from each other primarily by the age at which the skeletal lesions develop.…”

Section: Introductionmentioning

confidence: 99%

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Functional Analysis of the Single Nucleotide Polymorphism (787T>C) in the Tissue-Nonspecific Alkaline Phosphatase Gene Associated With BMD

Goseki‐Sone

Sogabe

Fukushi-Irie

et al. 2005

Journal of Bone and Mineral Research

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Polymorphisms of the TNSALP gene have not previously been studied as a possible determinant for variations in BMD or as a predisposing genetic factor for osteoporosis. This study showed a significantly higher association between the 787T>C (Tyr246His) TNSALP gene and BMD among 501 postmenopausal women. Furthermore, the effects of amino acid substitution on the catalytic property of the protein translated from the 787T>C gene were examined.Introduction: Alkaline phosphatase (ALP) is present mainly on the cell membrane in various tissues and hydrolyzes a variety of monophosphate esters into inorganic phosphoric acid and alcohol. Human ALPs are classified into four types: tissue-nonspecific, intestinal, placental, and germ cell types. Based on studies of hypophosphatasia, which is a systemic skeletal disorder resulting from a tissue-nonspecific ALP (TNSALP) deficiency, TNSALP was suggested to be indispensable for bone mineralization. Materials and Methods:We explored the possibility that the TNSALP gene may contribute to age-related bone loss in humans by examining the association between TNSALP gene polymorphisms and BMD in 501 Japanese postmenopausal women. To analyze the protein translated from the TNSALP gene associated with BMD, we constructed a TNSALP cDNA expression plasmid. Results: We genotyped two single nucleotide polymorphisms (787T>C[Tyr246His] and 876A>G[Pro275Pro]), which proved to be in complete linkage disequilibrium. There was a significant difference in BMD and the BMD score adjusted for age and body weight (Z score) among haplotypes (p ‫ס‬ 0.041), which was lowest among 787T/876A homozygotes, highest among 787T>C/876A>G homozygotes, and intermediate among heterozygotes. In subgroups divided by age, haplotypes were significantly associated with BMD in older postmenopausal women (>74 years; p ‫ס‬ 0.001), but not in younger postmenopausal women (<74 years; p ‫ס‬ 0.964). Expression of the 787T>C TNSALP gene using COS-1 cells showed that the protein translated from 787T>C had ALP-specific activity similar to that of 787T. Interestingly, the K m value for TNSALP in cells transfected with the 787T>C TNSALP gene was decreased significantly compared with that of cells bearing the 787T gene, reflecting the higher affinity. Conclusions: These results suggest that variation in TNSALP may be an important determinant of age-related bone loss in humans and that the phosphate metabolism pathway may provide a novel target for the prevention and treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Analysis of the Single Nucleotide Polymorphism (787T>C) in the Tissue-Nonspecific Alkaline Phosphatase Gene Associated With BMD

Goseki‐Sone

Sogabe

Fukushi-Irie

et al. 2005

Journal of Bone and Mineral Research

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“…These moderate alleles were defined on the basis of clinical status and/or transfection studies. When tested in vitro , moderate alleles produce significant residual alkaline phosphatase activity, while severe alleles do not usually have enzymatic activity (Fukushi et al, 1998; Zurutuza et al, 1999; Orimo et al, 2001; Watanabe et al, 2002; Ishida et al, 2003; Brun‐Heath et al, 2005; Watanabe et al, 2005; Collmann et al, 2009; Reibel et al, 2009). We previously reported that in odontohypophosphatasia, a mild form when compared to other moderate forms, 74% of the patients were heterozygous for an ALPL gene mutation, and only 26% carried two mutations (Fauvert et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

A Molecular‐Based Estimation of the Prevalence of Hypophosphatasia in the European Population

Mornet

Yvard

Taillandier

et al. 2011

Annals of Human Genetics

190

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SummaryThe prevalence of hypophosphatasia (HP), a rare metabolic disorder due to loss-of-function mutations in the ALPL gene, has never been estimated in the European population. Only one published study evaluated the incidence of severe HP at 1/100,000 in Canada 53 years ago. Moderate forms of hypophosphatasia (mHP), including HP with moderate bone features and the mildest form odontohypophosphatasia, reflect both recessive and dominant inheritance, and are therefore expected to be more frequent than severe forms of HP. Here we estimated both the prevalences of severe and mHP in European populations. The prevalence of severe HP was estimated at 1/300,000 on the basis of the number of cases tested in our laboratory and originating from France during the period 2000-2009. The prevalence of mHP was then estimated by using the proportion of dominant mutations among severe alleles and by estimating the penetrance of the disease in heterozygotes for dominant mutations. According to a genetic model with four alleles resulting in 10 distinct genotypes, the prevalence of dominant mHP in the European population was estimated to be 1/6370, pointing out that mHP is much more frequent than severe HP.

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“…HPP is an inherited disorder characterized by a defect in skeletal mineralization caused by TNSALP deficiency (30). Various mutations in the TNSALP gene have been analyzed (2,3,6,7,12,14,15,19,(23)(24)(25)(26)(27)(28). Elevated extracellular concentrations of inorganic pyrophosphate (PPi), phosphoethanolamine (PEA), and pyridoxal-5'-phosphate (PLP) have been observed in HPP (30).…”

Section: S][mentioning

confidence: 99%

Molecular effects of the tissue-nonspecific alkaline phosphatase gene polymorphism (787T > C) associated with bone mineral density

et al. 2008

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Based on studies of hypophosphatasia, which is a systemic skeletal disorder resulting from tissuenonspecific alkaline phosphatase (TNSALP) deficiency, TNSALP was suggested to be indispensable for bone mineralization. Recently, we demonstrated that there was a significant difference in bone mineral density (BMD) among haplotypes, which was lowest among TNSALP (787T [Tyr246Tyr]) homozygotes, highest among TNSALP (787T > C [Tyr246His]) homozygotes, and intermediate among heterozygotes. To analyze protein translated from the TNSALP gene 787T > C, we performed the biosynthesis of TNSALPs using TNSALP cDNA expression vectors. TNSALP (787T) and TNSALP (787T > C) were synthesized similarly as a high-mannose-type 66-kDa form, becoming an 80-kDa form. Expression of the human 787T > C TNSALP gene using the cultured mouse marrow stromal cell line ST2 demonstrated that the protein translated from 787T > C exhibited an ALP-specific activity similarly to that of 787T. Interestingly, the Km value for TNSALP in ST2 cells transfected with the 787T > C TNSALP gene was decreased significantly compared to that of cells carrying the 787T gene (P < 0.01). These results suggest that the significant difference in Km values between the proteins translated from 787T > C and 787T may contribute to regulatory effects on bone metabolism.Alkaline phosphatase (ALP; orthophosphoric monoester phospho-hydrolase, alkaline optimum, EC 3.1.3.1.) is classified into two types in most animals, excluding homonidae: tissue-nonspecific (liver/bone/ kidney; TNSALP) and intestinal types (29). In humans, there are at least four types of genetically differing isozymes: tissue-nonspecific, intestinal, placental, and germ cell types (11,18,29). The TNSALP gene (GenBank: NM_000478) is located on chromosome 1 and consists of 12 exons and 11 introns, with the coding sequence beginning in the second exon (29). TNSALP shows an approximately 50% homology with the other three isozymes (intestinal, placental, and germ cell). Their isozymes are tissue-specific and their genes are 90~98% homologous and clustered on chromosome 2 (11, 18). The core structures are largely conserved and exhibit the same metal ions and glycosylation sites in all mammalian ALPs. As a result of studies on cDNAs en-

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Function of Mutant (G1144A) Tissue-Nonspecific ALP Gene From Hypophosphatasia

Cited by 16 publications

References 24 publications

Functional Analysis of the Single Nucleotide Polymorphism (787T>C) in the Tissue-Nonspecific Alkaline Phosphatase Gene Associated With BMD

Functional Analysis of the Single Nucleotide Polymorphism (787T>C) in the Tissue-Nonspecific Alkaline Phosphatase Gene Associated With BMD

A Molecular‐Based Estimation of the Prevalence of Hypophosphatasia in the European Population

Molecular effects of the tissue-nonspecific alkaline phosphatase gene polymorphism (787T > C) associated with bone mineral density

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Function of Mutant (G1144A) Tissue-Nonspecific ALP Gene From Hypophosphatasia

Cited by 16 publications

References 24 publications

Functional Analysis of the Single Nucleotide Polymorphism (787T&gt;C) in the Tissue-Nonspecific Alkaline Phosphatase Gene Associated With BMD

Functional Analysis of the Single Nucleotide Polymorphism (787T&gt;C) in the Tissue-Nonspecific Alkaline Phosphatase Gene Associated With BMD

A Molecular‐Based Estimation of the Prevalence of Hypophosphatasia in the European Population

Molecular effects of the tissue-nonspecific alkaline phosphatase gene polymorphism (787T > C) associated with bone mineral density

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Product

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Functional Analysis of the Single Nucleotide Polymorphism (787T>C) in the Tissue-Nonspecific Alkaline Phosphatase Gene Associated With BMD

Functional Analysis of the Single Nucleotide Polymorphism (787T>C) in the Tissue-Nonspecific Alkaline Phosphatase Gene Associated With BMD