A molecular approach to dominance in hypophosphatasia

Lia-Baldini, Anne-Sophie; Müller, Françoise; Taillandier, A.; Gibrat, Jean‐François; Mouchard, M.; Robin, B.; Simon‐Bouy, Brigitte; Serre, J. L.; Aylsworth, Arthur S.; Bieth, Éric; Delanote, S.; Freisinger, Peter; Hu, Jiaxiang; Krohn, H. P.; Nuñes, Mark E.; Mornet, Étienne

doi:10.1007/s004390100546

Cited by 91 publications

(68 citation statements)

References 25 publications

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“…However, the homodimeric structure of the enzyme could make possible a dominant negative effect of the mutations, although these are rare in metabolic diseases. However, some forms of hypophosphatasia (MIM 146300, 241500, 241510) and also of cortisone reductase deficiency (MIM 604931) can be transmitted in a dominant manner and in these cases the mutations can exhibit a dominantnegative effect by inhibiting the enzymatic activity of the heterodimer (Lawson et al 2011;Lia-Baldini et al 2001). …”

Section: Discussionmentioning

confidence: 99%

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

et al. 2012

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The inherited 5-oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione (GSH) metabolism: the glutathione synthetase (GSS) and the 5-oxoprolinase (OPLAH). The GSS deficiency is the best characterized of the inborn errors of GSH metabolism, whereas the OPLAH deficiency is questioned whether it is a disorder or just a biochemical condition with no adverse clinical effects. Recently, the first human OPLAH mutation (p.H870Pfs) was reported in homozygosis in two siblings who suffered from 5-oxoprolinuria with a benign clinical course. We report two unrelated patients who manifested massive excretion of 5-oxoproline in urine. In both probands, the blood GSH levels were normal and no mutations were found in the GSS gene. The mutational screening of the OPLAH gene, which included the codified sequences, the intronic flanking sequences, the promoter sequence, and a genetic analysis in order to detect large deletions and/or duplications, showed that each patient only harbors one missense mutation in heterozygosis. The in silico analyses revealed that each one of these OPLAH mutations, p.S323R and p.V1089I, could alter the proper function of this homodimeric enzyme. In addition, clinical symptoms manifest in these two probands were not related to GSH cycle defects and, therefore, this study provides further evidence that oxoprolinuria may present as epiphenomenon in several pathological conditions and confound the final diagnosis.

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Section: Discussionmentioning

confidence: 99%

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

et al. 2012

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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: 92%

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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“…Kiminitsu Oda et al demonstrated that the p.A116T protein failed to fold properly and forms disulfide-bonded aggregates, though it was indeed capable of interacting with the WT and reaching the cell surface [18]. Furthermore, Beck et al revealed that the p.G63V and p.D378V mutants were concentrated in the subcellular region and had a dominant-negative effect on the WT TNSALP protein [15,29,30]. According to the structural features of the TNSALP protein, done with a 3D model, the TNSALP missense mutations associated with hypophosphatasia are classified as follows: 1) active site or active site vicinity, 2) active site valley, 3) homodimer interface, 4) crown domain, 5) calcium site or calcium site vicinity and 6) others [10].…”

Section: Discussionmentioning

confidence: 99%

Characterization of Six Missense Mutations in the Tissue-Nonspecific Alkaline Phosphatase (TNSALP) Gene in Chinese Children with Hypophosphatasia

Yang

Wang

Geng

et al. 2013

Cell Physiol Biochem

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Aims: Hypophosphatasia, a rare inherited disease characterized by defective mineralization of bone and teeth, is caused by various mutations in the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) gene. Our aim was to determine the mutations on TNSALP gene in three Chinese children diagnosed as having hypophosphatasia. Methods: Genomic DNA was extracted from whole blood samples of patients and their parents. The TNSALP coding regions were then sequenced. Plasmids expressing wild-type or various mutants were built and in vitro studies were performed in order to determine whether these amino acid replacements could affect the TNSALP enzymatic activity. Results: Six missense mutations were identified from three independent pedigrees. Of the six missense mutations, four were novel and two had been previously reported. The Y28D, A111T and T389N mutants displayed only negligible ALP activity in vitro compared to the wild-type (WT) TNSALP. The defect was mainly due to the significantly decreased protein expression in the 66 KD immature forms and the nearly undetectable protein expression in the 80 KD mature forms. Moreover, all three mutants had a dominant negative effect on the WT protein when co-transfected with TNSALP (WT). M219V and R136L mutants both exhibited partial enzymatic activities which were consistent with reduced protein expression in both forms of TNSALP which further exhibited moderate dominant-negative effect. In addition, Y388H mutant showed weak ALP activity. Western blot analysis indicated that the extreme reduction in signal from the mature forms of TNSALP could be the main cause of decreased enzymatic activity, since a strong signal was observed in the immature forms. Conclusion: Six missense mutations were identified in three Chinese hypophosphatasia pedigrees with subnormal serum ALP activity. Our results show that the low activity of serum ALP in the three patients is due mainly to a defect in the protein expression of the mutants. This may be the underling molecular mechanism for hypophosphatasia in these patients.

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A molecular approach to dominance in hypophosphatasia

Cited by 91 publications

References 25 publications

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

Hypophosphatasia: an overview of the disease and its treatment

Characterization of Six Missense Mutations in the Tissue-Nonspecific Alkaline Phosphatase (TNSALP) Gene in Chinese Children with Hypophosphatasia

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