title: Age-related macular degeneration-associated silent polymorphisms in HtrA1 impair its ability to antagonize insulin-like growth factor 1.
abstract: Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD.
authors.affiliation: Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
authors.forename: Sarah Melissa P
authors.initials: SM
authors.lastname: Jacobo
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Deangelis
authors.forename: Ivana K
authors.initials: IK
authors.lastname: Kim
authors.forename: Andrius
authors.initials: A
authors.lastname: Kazlauskas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006720:Homozygote; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D059748:Proteolysis; D017451:Receptors, Somatomedin / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction; D014357:Trypsin / Q000737:chemistry
chemical_list: D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D014357:Trypsin