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PLoS One. 2013 Dec 17;8(12):e82554. doi: 10.1371/journal.pone.0082554. eCollection 2013.

Polymorphisms of CYP51A1 from cholesterol synthesis: associations with birth weight and maternal lipid levels and impact on CYP51 protein structure.

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Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Laboratory of Biomolecular Structure, National Institute of Chemistry Slovenia, Ljubljana, Slovenia.
Laboratory of Biomolecular Structure, National Institute of Chemistry Slovenia, Ljubljana, Slovenia ; EN-FIST Centre of Excellence, Ljubljana, Slovenia.
Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America.


We investigated the housekeeping cytochrome P450 CYP51A1 encoding lanosterol 14α-demethylase from cholesterol synthesis that was so far not directly linked to human disorders. By direct sequencing of CYP51A1 in 188 women with spontaneous preterm delivery and 188 unrelated preterm infants (gestational age <37 weeks) we identified 22 variants where 10 are novel and rare. In infants there were two novel CYP51A1 variants where damaging effects of p.Tyr145Asp from the substrate recognition region, but not p.Asn193Asp, were predicted by PolyPhen2 and SIFT. This was confirmed by molecular modeling showing that Tyr145Asp substitution results in changed electrostatic potential of the CYP51 protein surface and lengthened distance to the heme which prevents hydrogen bonding. The CYP51 Tyr145Asp mutation is rare and thus very interesting for further structure/function relationship studies. From the 12 identified known variants rs6465348 was chosen for family based association studies due to its high minor allele frequency. Interestingly, this CYP51A1 common variant associates with small for gestational age weight in newborns (p = 0.028) and lower blood total cholesterol and low density lipoprotein cholesterol levels in mothers in 2nd trimester of pregnancy (p = 0.042 and p = 0.046 respectively). Our results indicate a new link between a cholesterol synthesis gene CYP51A1 and pregnancy pathologies.

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