Alpha 2.0
Login Register
» Articles » PMID: 18340466

A New Mechanism of Dominance in Hypophosphatasia: the Mutated Protein Can Disturb the Cell Localization of the Wild-type Protein

Overview
Journal Hum Genet
Specialty Genetics
Date 2008 Mar 15
PMID 18340466
Citations 17
Authors
A S Lia-Baldini
I Brun-Heath
C Carrion
B Simon-Bouy
J L Serre
M E Nunes
E Mornet
Affiliations
Soon will be listed here.
Abstract

The dominant negative effect of mutations is rare in metabolic diseases and its mechanism has not been studied much. Hypophosphatasia, a bone inherited metabolic disorder, is a good model because the disease can be dominantly transmitted. The gene product activity depends on a homodimeric configuration and many mutations have been reported in the ALPL gene responsible for the disease. Using CFP/YFP-tagged-TNSALP plasmids, transfections in COS cells and confocal fluorescence analyses, we studied the point mutation G232V (c.746G>T). We showed that the G232V protein sequestrates some of the wild-type protein into the cells and prevents it from reaching the membrane where it plays its physiological role.

Citing Articles

Newborn screening for hypophosphatasia: development of a high-throughput tissue nonspecific alkaline phosphatase activity assay using dried blood spots.

Noda Y, Kido J, Sawada T, Tanaka K, Kumeda K, Yoshida S JBMR Plus. 2025; 9(3):ziae172.

PMID: 39925621 PMC: 11803525. DOI: 10.1093/jbmrpl/ziae172.

Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia.

Cinque L, Pugliese F, Salcuni A, Trombetta D, Battista C, Biagini T Front Endocrinol (Lausanne). 2023; 14:1205977.

PMID: 37600704 PMC: 10433156. DOI: 10.3389/fendo.2023.1205977.

The First Large Deletion of Identified in a Patient Presenting with a Sensory Polyneuropathy.

Pyromali I, Richard L, Derouault P, Vallat J, Ghorab K, Magdelaine C Biomedicines. 2023; 11(6).

PMID: 37371660 PMC: 10295399. DOI: 10.3390/biomedicines11061565.

Clinical and Genetic Characteristics of Pediatric Patients with Hypophosphatasia in the Russian Population.

Glotov O, Savostyanov K, Nagornova T, Chernov A, Fedyakov M, Raspopova A Int J Mol Sci. 2022; 23(21).

PMID: 36361766 PMC: 9654387. DOI: 10.3390/ijms232112976.

Disorders of phosphate homeostasis in children, part 1: primer on mineral ion homeostasis and the roles of phosphate in skeletal biology.

Shore R Pediatr Radiol. 2022; 52(12):2278-2289.

PMID: 35536415 DOI: 10.1007/s00247-022-05374-y.

References
1.
Hoylaerts M, Manes T, Millan J . Mammalian alkaline phosphatases are allosteric enzymes. J Biol Chem. 1997; 272(36):22781-7. DOI: 10.1074/jbc.272.36.22781. View
2.
Muller H, Yamazaki M, Michigami T, Kageyama T, Schonau E, Schneider P . Asp361Val Mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild-type enzyme. J Clin Endocrinol Metab. 2000; 85(2):743-7. DOI: 10.1210/jcem.85.2.6373. View
3.
Ito M, Amizuka N, Ozawa H, Oda K . Retention at the cis-Golgi and delayed degradation of tissue-non-specific alkaline phosphatase with an Asn153-->Asp substitution, a cause of perinatal hypophosphatasia. Biochem J. 2002; 361(Pt 3):473-80. PMC: 1222329. DOI: 10.1042/0264-6021:3610473. View
4.
Baumgartner M . Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency. J Inherit Metab Dis. 2005; 28(3):301-9. DOI: 10.1007/s10545-005-7054-3. View
5.
Lia-Baldini A, Muller F, Taillandier A, Gibrat J, Mouchard M, Robin B . A molecular approach to dominance in hypophosphatasia. Hum Genet. 2001; 109(1):99-108. DOI: 10.1007/s004390100546. View