Universität zu Köln

Stella, Jacqueline, Buers, Insa, van de Wetering, Koen, Hoehne, Wolfgang, Rutsch, Frank and Nitschke, Yvonne (2016). Effects of Different Variants in the ENPP1 Gene on the Functional Properties of Ectonucleotide Pyrophosphatase/Phosphodiesterase Family Member 1. Hum. Mutat., 37 (11). S. 1190 - 1202. HOBOKEN: WILEY-BLACKWELL. ISSN 1098-1004

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Abstract

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (E-NPP1), encoded by ENPP1, is a plasma membrane protein that generates inorganic pyrophosphate (PPi), a physiologic inhibitor of hydroxyapatite formation. In humans, variants in ENPP1 are associated with generalized arterial calcification of infancy, an autosomal-recessive condition causing premature onset of arterial calcification and intimal proliferation resulting in stenoses. ENPP1 variants also cause pseudoxanthoma elasticum characterized by ectopic calcification of soft connective tissues. To determine the functional impact of ENPP1 missense variants, we analyzed 13 putative pathogenic variants in vitro regarding their functional properties, that is, activity, localization, and PPi generation. Transfection of eight of the 13 variants led to complete loss of NPP activity, whereas four mutants (c.1412A > G, p.Tyr471Cys; c.1510A > C, p.Ser504Arg; c.1976A > G, p.Tyr659Cys; c.2330A > G, p.His777Arg) showed residual activity compared with wild-type E-NPP1. One putative pathologic variant (c.2462 G > A, p.Arg821His) showed normal activity. The five mutants with normal or residual E-NPP1 enzyme activity were still able to generate PPi and localized in the plasma membrane. In this study, we identified a functional ENPP1 polymorphism, which was expected to be pathogenic till now. Furthermore, we identified four mutants (p.Tyr471Cys, p.Ser504Arg, p.Tyr659Cys, p.His777Arg) with residual E-NPP1 function, which would be potential therapeutical targets for conformational-stabilizing agents.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stella, Jacqueline UNSPECIFIED UNSPECIFIED UNSPECIFIED Buers, Insa UNSPECIFIED UNSPECIFIED UNSPECIFIED van de Wetering, Koen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehne, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Rutsch, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Nitschke, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-257442
DOI:	10.1002/humu.23057
Journal or Publication Title:	Hum. Mutat.
Volume:	37
Number:	11
Page Range:	S. 1190 - 1202
Date:	2016
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1098-1004
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language IDIOPATHIC ARTERIAL CALCIFICATION; POSTERIOR LONGITUDINAL LIGAMENT; CELL MEMBRANE GLYCOPROTEIN-1; PSEUDOXANTHOMA ELASTICUM; NUCLEOTIDE PYROPHOSPHATASES/PHOSPHODIESTERASES; INORGANIC PYROPHOSPHATE; ALKALINE-PHOSPHATASE; BONE MINERALIZATION; K121Q POLYMORPHISM; INSULIN-RECEPTOR Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25744