Severe hypercalcaemia and respiratory insufficiency associated with infantile hypophosphatasia caused by two novel mutations of the tissue-nonspecific alkaline phosphatase gene

Mochizuki, Hidetaka; Saito, Mariko; Michigami, Toshimi; Ohashi, Hirofumi; Koda, Naoya; Yamaguchi, Shuichi; Ozono, Keiichi

doi:10.1007/s004310051290

Cited by 29 publications

(13 citation statements)

References 18 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: 76%

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: 76%

A molecular approach to dominance in hypophosphatasia

et al. 2001

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“…Because 1559delT has never been described in patients from North America [2][3][4][5] and Europe [12][13][14][15][16], this deletion appears to be frequent only among Japanese patients. Recently, a patient with a Japanese mother and an American father and inherited a K207E mutation from the mother has been described [11]. Even if this patient of mixed ethnic origin were added to the Japanese cases, the allele frequency of 1559delT would be still high (34%).…”

Section: Discussionmentioning

confidence: 97%

“…The molecular bases that determine the clinical types have not been sufficiently elucidated. To date, 71 mutations in the TNSALP gene have been described in North American [2][3][4][5], Japanese [6][7][8][9][10][11], and European [12][13][14][15][16] patients with hypophosphatasia. In those reports, a deletion of T at nucleotide 1559 has been detected only in Japanese patients [6,9,10], suggesting that the deletion may be frequent among them.…”

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confidence: 98%

Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia

Orimo

Goseki‐Sone

Inoue

et al. 2002

Journal of Bone and Mineral Metabolism

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The tissue-nonspecific alkaline phosphatase (TNSALP) gene in four unrelated patients with hypophosphatasia was analyzed using polymerase chain reaction-single strand conformation polymorphism and the direct sequencing method. Of the participating patients, one had childhood-type and three had perinatal-type disease. All carried a deletion of T at cDNA number 1559, which causes a frameshift downstream from codon L503, as a heterozygote. In the childhood-type patient, an F310L mutation was detected in the opposite allele. Similarly, a perinatal-type patient carried a V3651 mutation in the opposite allele. Mutations in the opposite alleles were not detected in the other two patients with perinatal-type disease. In addition, although both parents carried the deletion as a heterozygote in two families with childhood-type and perinatal-type disease, patients from those families were not homozygous for the deletion. Several single-nucleotide polymorphisms (SNPs) were also detected, which were shown to be useful for haplotype analysis. Allele frequency of the deletion among Japanese patients was 36% (10 of 28 alleles) but none occurred in Caucasian patients. These findings indicate that regardless of clinical type, deletion in the TNSALP gene occurs frequently among Japanese patients. Furthermore, haplotype analysis using SNPs suggested that the deletion might have derived from more than a single founder.

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“…On the other hand, hypercalcemia is frequent in HPP patients, particularly in those with the infantile form of the disease (5,6,7). Hypercalcemia is thought to be due to impaired bone mineralization in the presence of normal bone resorption.…”

Section: Discussionmentioning

confidence: 99%

Hypophosphatasia Presenting with Pyridoxine-Responsive Seizures, Hypercalcemia, and Pseudotumor Cerebri: Case Report

Demirbilek¹,

Alanay²,

Alikaşifoğlu³

et al. 2012

jcrpe

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Hypophosphatasia (HPP) is an inborn error of metabolism characterized by defective bone mineralization caused by a deficiency in alkaline phosphatase (ALP) activity due to mutations in the tissue-nonspecific ALP (TNALP) gene. The clinical expression of the disease is variable. Six forms of HPP are identified according to age at presentation and clinical features. Patients with the infantile form are normal at birth. First symptoms appear within the first 6 months of life. Along with skeletal findings, HPP patients may present with hypercalcemia, seizures, pseudotumor cerebri, and pulmonary insufficiency. Seizures in HPP are refractory to conventional antiepileptic drugs, but are responsive to pyridoxine. Herein, we report a case of HPP who presented with pyridoxine-responsive seizures in the early neonatal period and was found to have hypercalcemia, skeletal demineralization and increased intracranial pressure. Key words: Hypophosphatasia, pyridoxine-responsive seizures, bisphosphonates, alkaline phosphatase, bone resorption, hypercalcemia Conflict of interest:None declared.

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Severe hypercalcaemia and respiratory insufficiency associated with infantile hypophosphatasia caused by two novel mutations of the tissue-nonspecific alkaline phosphatase gene

Abstract: The detection of tissue-nonspecific alkaline phosphatase gene mutations and expression studies to determine the enzymatic activity of mutant gene products was useful for assessing the clinical course of this patient with hypophosphatasia.

Cited by 29 publications

References 18 publications

A molecular approach to dominance in hypophosphatasia

A molecular approach to dominance in hypophosphatasia

Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia

Hypophosphatasia Presenting with Pyridoxine-Responsive Seizures, Hypercalcemia, and Pseudotumor Cerebri: Case Report

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