Glycosylation-deficient mutations in tissue-nonspecific alkaline phosphatase impair its structure and function and are linked to infantile hypophosphatasia

The FEBS Journal
Keiichi KomaruKimimitsu Oda

Abstract

Tissue-nonspecific alkaline phosphatase (TNSALP) is a membrane glycoprotein with a proposed role in bone mineralisation. Indeed, mutations in TNSALP have been identified in patients with hypophosphatasia (HPP), a genetic disease characterized by hypomineralization of bone and teeth and a deficiency in serum ALP activity. TNSALP has five potential N-glycosylation sites at N140, N230, N271, N303, and N430 by standard nomenclature. A mutation at one of these sites, N430, was recently detected in a patient with infantile HPP. Using site-directed mutagenesis, we demonstrated that TNSALP has five N-glycans in transfected COS-1 cells and that individual single N-glycan deletion mutants of TNSALP retain the dimeric structure required for ALP activity, excluding the possibility that any single N-glycan plays a vital role in the structure and function of TNSALP. However, we found that TNSALP (N430Q) and TNSALP (N430E) mutants, but not a TNSALP (N430D) mutant, failed to form dimers. The TNSALP (N430S) mutant linked to infantile HPP was glycosylation-defective and unable to dimerise, similar to TNSALP (N430Q) and TNSALP (N430E) mutants; therefore, TNSALP (N430S) was established as a severe allele without strong ALP activity. In contrast to...Continue Reading

References

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May 20, 1999·Human Molecular Genetics·L ZurutuzaE Mornet
Sep 9, 2006·Cell·Kazuaki Ohtsubo, Jamey D Marth
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May 12, 2009·Glycobiology·Ajit Varki

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Citations

Dec 14, 2017·Journal of Bone and Mineral Metabolism·Agnès TaillandierEtienne Mornet
Nov 11, 2019·Calcified Tissue International·Toshimi MichigamiKeiichi Ozono
Aug 11, 2019·Journal of Oral Biosciences·Keiichi KomaruKimimitsu Oda

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