A1 Refereed original research article in a scientific journal
Funtional characterization of four novel MAN2B1 mutations causing juvenile onset alpha-mannosidosis
Authors: Pittis MG, Montalvo ALE, Heikinheimo P, Sbaragli M, Balducci C, Persichetti E, Van Maldergem L, Filocamo M, Bembi B, Beccari T
Publisher: ELSEVIER SCIENCE BV
Publication year: 2007
Journal:: Clinica Chimica Acta
Journal name in source: CLINICA CHIMICA ACTA
Journal acronym: CLIN CHIM ACTA
Volume: 375
Issue: 1-2
First page : 136
Last page: 139
Number of pages: 4
ISSN: 0009-8981
DOI: https://doi.org/10.1016/j.cca.2006.06.034
Abstract
Alpha-mannosidosis is a recessively inherited disorder due to the deficiency of the lysosomal alpha-mannosidase. We report the molecular analysis performed in two patients with the late onset form of alpha-mannosidosis. Four new alleles were identified: three missense mutations involving highly conserved residues, c.597 C > A (p.H200N), c. 1553 T > C (p.L518P) and c.2746 C > A (p.R916S) and a single nucleotide deletion, c.2660delC. In vitro expression studies in COS-1 cells demonstrated that pH200N, p.L518P and p.R916S proteins are expressed but retained no residual enzyme activity. These data are supported by structural 3D analysis which predicted that both p.L518P and p.R916S could affect the interaction of the small E-domain with the active site domain or the main body of the structure while the pH200N might alter substrate binding or other catalytic properties. Finally, the c.2660delC causes a frameshift introducing a premature stop codon (p.T887SfsX45), presuming to be a severe mutation. (c) 2006 Published by Elsevier B.V.
Alpha-mannosidosis is a recessively inherited disorder due to the deficiency of the lysosomal alpha-mannosidase. We report the molecular analysis performed in two patients with the late onset form of alpha-mannosidosis. Four new alleles were identified: three missense mutations involving highly conserved residues, c.597 C > A (p.H200N), c. 1553 T > C (p.L518P) and c.2746 C > A (p.R916S) and a single nucleotide deletion, c.2660delC. In vitro expression studies in COS-1 cells demonstrated that pH200N, p.L518P and p.R916S proteins are expressed but retained no residual enzyme activity. These data are supported by structural 3D analysis which predicted that both p.L518P and p.R916S could affect the interaction of the small E-domain with the active site domain or the main body of the structure while the pH200N might alter substrate binding or other catalytic properties. Finally, the c.2660delC causes a frameshift introducing a premature stop codon (p.T887SfsX45), presuming to be a severe mutation. (c) 2006 Published by Elsevier B.V.
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