Purchase this article with an account.
Lisa A. Kuttner-Kondo; Sequences Resembling Human Complement Factor H-Like 1 (FHL1) in Macaques have Amino Acid Variations in Complement Control Protein Repeats (CCPs) 6 and 7 that Occur Near the Site Linked to Human Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2011;52(14):2344.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The Tyr402His substitution in the human regulator of complement activation, complement factor H (CFH), that is associated with age-related macular degeneration (AMD) resides in complement control protein repeat (CCP) 7. 402His is a critical residue within a glycan binding site composed of amino acids from CCPs 6 and 7. Currently, it is not known if amino acid variation in the same region of macaque CFH or its alternative splice variant CFH-like 1 (FHL1) plays a role in the early- or later-onset forms of macular degeneration seen in some macaques. As a starting point, to identify amino acid variations in the CCPs 6 and 7 domain of macaque CFH, we sequenced the predicted FHL1 in phenotypically uncharacterized macaques.
Total liver RNA from a rhesus macaque and 3 cynomolgus monkeys was used in RT-PCR reactions to find cDNA resembling human FHL1. A forward primer in the 5-prime untranslated region and 2 reverse primers in the intron following CCP 7 of the predicted rhesus macaque CFH-like gene (found in Macaca mulatta chromosome 1, Mmul_051212, whole genome shotgun sequence, NC_007858.1) were designed to capture the nucleotides corresponding to the predicted complete amino acid sequence of the alternative splice product. The CCPs 6 and 7 sequences obtained were compared with the same domain in the predicted full-length rhesus macaque CFH-like transcript variant 3 (LOC717346) XM_001111875.2 and two short mRNA ESTs, rhesus macaque CO582090.1 and pigtail macaque DR774132.1.
Considerable similarity is present in these macaque CFH-like/FHL1 CCPs 6 and 7 sequences. However, amino acid variations were found at 4 positions in CCP 6, and 7 positions in CCP 7. Amino acid variation at residues 360, 392, 401 and 403 are in or adjacent to the human CFH, AMD-associated glycan binding site identified in 2007 by Prosser et al. (J. Exp. Med. 204:2277) which contains residue 402. Residues 360 and 392 may be a proline or a histidine, residue 401 may be an asparagine or a tyrosine, and residue 403 may be a glycine or an arginine. Variation at residues 352, 356, and 373 are in or near another human CFH sulfated sugar binding site.
These amino acid differences may have a significant effect on how the macaque complement regulator responds to its environment. The variable macaque sequences provide insights into the evolution of this important domain of CFH which in humans has both AMD and pathogen associations.
This PDF is available to Subscribers Only