title: Functional consequences of a novel variant of PCSK1.
abstract: BACKGROUND
  Common single nucleotide polymorphisms (SNPs) in proprotein convertase subtilisin/kexin type 1 with modest effects on PC1/3 in vitro have been associated with obesity in five genome-wide association studies and with diabetes in one genome-wide association study. We here present a novel SNP and compare its biosynthesis, secretion and catalytic activity to wild-type enzyme and to SNPs that have been linked to obesity.
  
  
  RESULTS
  A novel PC1/3 variant introducing an Arg to Gln amino acid substitution at residue 80 (within the secondary cleavage site of the prodomain) (rs1799904) was studied. This novel variant was selected for analysis from the 1000 Genomes sequencing project based on its predicted deleterious effect on enzyme function and its comparatively more frequent allele frequency. The actual existence of the R80Q (rs1799904) variant was verified by Sanger sequencing. The effects of this novel variant on the biosynthesis, secretion, and catalytic activity were determined; the previously-described obesity risk SNPs N221D (rs6232), Q665E/S690T (rs6234/rs6235), and the Q665E and S690T SNPs (analyzed separately) were included for comparative purposes. The novel R80Q (rs1799904) variant described in this study resulted in significantly detrimental effects on both the maturation and in vitro catalytic activity of PC1/3.
  
  
  CONCLUSIONS
  Our findings that this novel R80Q (rs1799904) variant both exhibits adverse effects on PC1/3 activity and is prevalent in the population suggests that further biochemical and genetic analysis to assess its contribution to the risk of metabolic disease within the general population is warranted.
authors: Department of Anatomy and Neurobiology, University of Maryland-Baltimore, Baltimore, MD, USA.
authors: Lindsay A
authors: LA
authors: Pickett
authors: Michael
authors: M
authors: Yourshaw
authors: Valeria
authors: V
authors: Albornoz
authors: Zijun
authors: Z
authors: Chen
authors: R Sergio
authors: RS
authors: Solorzano-Vargas
authors: Stanley F
authors: SF
authors: Nelson
authors: Martín G
authors: MG
authors: Martín
authors: Iris
authors: I
authors: Lindberg
mesh_terms: D055162:Biocatalysis; D030541:Databases, Genetic; D003920:Diabetes Mellitus / Q000235:genetics; D005260:Female; D006801:Humans; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013329:Structure-Activity Relationship
chemical_list: D009479:Neuropeptides; C403532:PCSK1N protein, human
references: BMC Med Genet. 2010 Jun 09;11:86
references: 20534142
references: Genome Res. 2010 Sep;20(9):1297-303
references: 20644199
references: Am J Hum Genet. 2011 Apr 8;88(4):440-9
references: 21457909
references: J Mol Biol. 2002 Jul 19;320(4):801-12
references: 12095256
references: Genomics. 1991 Sep;11(1):103-7
references: 1765368
references: J Neurochem. 2003 Jun;85(6):1592-603
references: 12787078
references: J Neurosci. 1993 Mar;13(3):1258-79
references: 8441010
references: J Biol Chem. 1995 Oct 20;270(42):24702-6
references: 7559585
references: Biochemistry. 1997 Dec 23;36(51):16309-20
references: 9405066
references: Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8822-6
references: 1528899
references: Mol Genet Metab. 2011 Dec;104(4):682-7
references: 22000902
references: Trends Genet. 2000 May;16(5):198-200
references: 10782110
references: Hum Mol Genet. 2006 Jun 1;15(11):1884-93
references: 16644867
references: Nat Genet. 2008 Aug;40(8):943-5
references: 18604207
references: Hum Mol Genet. 2001 Mar 15;10(6):591-7
references: 11230178
references: Biochem J. 1993 Sep 15;294 ( Pt 3):735-43
references: 8397508
references: Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
references: 12824425
references: Nature. 2010 Oct 28;467(7319):1061-73
references: 20981092
references: J Endocrinol. 2005 Feb;184(2):291-318
references: 15684339
references: J Biol Chem. 2000 Dec 15;275(50):39213-22
references: 10995742
references: Nucleic Acids Res. 2001 Jan 1;29(1):308-11
references: 11125122
references: J Biol Chem. 1997 Dec 26;272(52):32810-6
references: 9407057
references: Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5297-301
references: 1647029
references: Endocrinology. 2006 Apr;147(4):1621-31
references: 16384863
references: Biochem J. 2004 May 1;379(Pt 3):757-63
references: 14741044
references: Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
references: 12202775
references: J Biol Chem. 2006 Dec 15;281(50):38867-70
references: 17050541
references: Diabetes. 2011 Oct;60(10):2624-34
references: 21873549
references: Mol Endocrinol. 1995 Jan;9(1):3-13
references: 7760848
references: Proc Natl Acad Sci U S A. 1991 May 1;88(9):3564-8
references: 2023902
references: Methods Mol Biol. 1996;57:31-44
references: 8849992
references: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10293-8
references: 12145326
references: Biochem Biophys Res Commun. 1994 Jun 15;201(2):795-804
references: 8003017
references: J Clin Invest. 2003 Nov;112(10):1550-60
references: 14617756
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D800-6
references: 21045057
references: Annu Rev Genomics Hum Genet. 2006;7:61-80
references: 16824020
references: J Neurochem. 1998 Apr;70(4):1670-8
references: 9523585
references: Diabetes. 2012 Feb;61(2):383-90
references: 22210313
references: J Biol Chem. 2006 Mar 17;281(11):7556-67
references: 16407210
references: Biochem Biophys Res Commun. 2000 Jan 27;267(3):940-2
references: 10673395
references: J Endocrinol. 2004 Aug;182(2):353-64
references: 15283695
references: Mol Endocrinol. 1992 Jul;6(7):1088-94
references: 1508222
references: EMBO J. 1997 Apr 1;16(7):1508-18
references: 9130696
references: J Neurosci. 1997 Jan 15;17(2):563-75
references: 8987779
references: Genome Res. 2002 Mar;12(3):436-46
references: 11875032
references: J Biol Chem. 1995 Feb 10;270(6):2695-702
references: 7852339
references: Nat Genet. 1997 Jul;16(3):303-6
references: 9207799
references: Nature. 2004 Oct 21;431(7011):931-45
references: 15496913
references: J Clin Endocrinol Metab. 2007 Sep;92(9):3369-73
references: 17595246
references: J Biol Chem. 1994 Jul 1;269(26):17440-7
references: 8021247
references: Nat Protoc. 2009;4(7):1073-81
references: 19561590