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Genetic analysis of complement factor H related 5, CFHR5, in patients with age-related macular degeneration.

Narendra U, Pauer GJ, Hagstrom SA - Mol. Vis. (2009)

Bottom Line: Val379Leu, Met514Arg, and Cys568Ter were found only in normal controls.No definitive pathogenic CFHR5 mutations have been found in any of 639 unrelated patients with AMD, indicating that sequence variations in CFHR5 do not play a major role in determining AMD susceptibility.However, our findings suggest a possible protective role for Asp169Asp.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

ABSTRACT

Purpose: To investigate the complement factor H related 5 (CFHR5) gene, encoding a member of the complement factor H family, for the presence of genetic polymorphisms or mutations associated with age-related macular degeneration (AMD).

Methods: We screened 639 unrelated patients with AMD and 663 age-matched normal controls using direct genomic sequencing of the ten coding exons, along with the immediately flanking intronic DNA. The pathologic impact of the identified sequence variants were analyzed by computational methods using PolyPhen and PMut algorithms.

Results: We identified five heterozygous sequence changes in CFHR5. Asp169Asp had a minor allele frequency of 0.001% in patients and 0.014% in controls (p<0.0001), while Arg356His had a minor allele frequency of 0.016% in patients and 0.007% in controls. Val379Leu, Met514Arg, and Cys568Ter were found only in normal controls. In silico analysis predicted Arg356His and Val379Leu to be neutral and benign. Met514Arg was predicted to be pathological and damaging to the function of the CFHR5 protein.

Conclusions: No definitive pathogenic CFHR5 mutations have been found in any of 639 unrelated patients with AMD, indicating that sequence variations in CFHR5 do not play a major role in determining AMD susceptibility. However, our findings suggest a possible protective role for Asp169Asp. Further studies of different and larger populations of patient and control samples will be required to address this observation.

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Related in: MedlinePlus

Schematic representation of the genomic structures of the genes in the CFH gene family. The CFH family is composed of several distinct proteins that lie in a gene cluster on chromosome 1. Structurally, these proteins are similar. They each contain several functional domains called short consensus repeats (SCRs), which are drawn as ovals in this illustration. The interacting proteins for some of these SCRs have been determined and are shown at the top. Abbreviations: C reactive protein (CRP); heparin (Hep).
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f1: Schematic representation of the genomic structures of the genes in the CFH gene family. The CFH family is composed of several distinct proteins that lie in a gene cluster on chromosome 1. Structurally, these proteins are similar. They each contain several functional domains called short consensus repeats (SCRs), which are drawn as ovals in this illustration. The interacting proteins for some of these SCRs have been determined and are shown at the top. Abbreviations: C reactive protein (CRP); heparin (Hep).

Mentions: Several regulators of complement activation, including CFH, lie in a gene cluster and have been mapped to chromosome 1q32. An evaluation of AMD genome-wide scans reveals that the strongest linkage to AMD is on chromosome 1q25–32 [8]. This array includes genes that encode the seven proteins in the CFH family (Figure 1). Structurally, these proteins are similar, each being built on a motif of distinct functional domains typical of the regulators of complement activation called short consensus repeats (SCRs). The interacting partners with some of these SCRs include C reactive protein (CRP), C3b, and heparin [9]. CFH-like 1 (CFHL1) is a splice isoform of CFH, while complement factor H-related proteins 1–5 (CFHR1–5) are each encoded by a unique gene (CFHR1–5). The SCRs of CFHR1–5 are similar to some of the SCRs in CFH [10].


Genetic analysis of complement factor H related 5, CFHR5, in patients with age-related macular degeneration.

Narendra U, Pauer GJ, Hagstrom SA - Mol. Vis. (2009)

Schematic representation of the genomic structures of the genes in the CFH gene family. The CFH family is composed of several distinct proteins that lie in a gene cluster on chromosome 1. Structurally, these proteins are similar. They each contain several functional domains called short consensus repeats (SCRs), which are drawn as ovals in this illustration. The interacting proteins for some of these SCRs have been determined and are shown at the top. Abbreviations: C reactive protein (CRP); heparin (Hep).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667568&req=5

f1: Schematic representation of the genomic structures of the genes in the CFH gene family. The CFH family is composed of several distinct proteins that lie in a gene cluster on chromosome 1. Structurally, these proteins are similar. They each contain several functional domains called short consensus repeats (SCRs), which are drawn as ovals in this illustration. The interacting proteins for some of these SCRs have been determined and are shown at the top. Abbreviations: C reactive protein (CRP); heparin (Hep).
Mentions: Several regulators of complement activation, including CFH, lie in a gene cluster and have been mapped to chromosome 1q32. An evaluation of AMD genome-wide scans reveals that the strongest linkage to AMD is on chromosome 1q25–32 [8]. This array includes genes that encode the seven proteins in the CFH family (Figure 1). Structurally, these proteins are similar, each being built on a motif of distinct functional domains typical of the regulators of complement activation called short consensus repeats (SCRs). The interacting partners with some of these SCRs include C reactive protein (CRP), C3b, and heparin [9]. CFH-like 1 (CFHL1) is a splice isoform of CFH, while complement factor H-related proteins 1–5 (CFHR1–5) are each encoded by a unique gene (CFHR1–5). The SCRs of CFHR1–5 are similar to some of the SCRs in CFH [10].

Bottom Line: Val379Leu, Met514Arg, and Cys568Ter were found only in normal controls.No definitive pathogenic CFHR5 mutations have been found in any of 639 unrelated patients with AMD, indicating that sequence variations in CFHR5 do not play a major role in determining AMD susceptibility.However, our findings suggest a possible protective role for Asp169Asp.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

ABSTRACT

Purpose: To investigate the complement factor H related 5 (CFHR5) gene, encoding a member of the complement factor H family, for the presence of genetic polymorphisms or mutations associated with age-related macular degeneration (AMD).

Methods: We screened 639 unrelated patients with AMD and 663 age-matched normal controls using direct genomic sequencing of the ten coding exons, along with the immediately flanking intronic DNA. The pathologic impact of the identified sequence variants were analyzed by computational methods using PolyPhen and PMut algorithms.

Results: We identified five heterozygous sequence changes in CFHR5. Asp169Asp had a minor allele frequency of 0.001% in patients and 0.014% in controls (p<0.0001), while Arg356His had a minor allele frequency of 0.016% in patients and 0.007% in controls. Val379Leu, Met514Arg, and Cys568Ter were found only in normal controls. In silico analysis predicted Arg356His and Val379Leu to be neutral and benign. Met514Arg was predicted to be pathological and damaging to the function of the CFHR5 protein.

Conclusions: No definitive pathogenic CFHR5 mutations have been found in any of 639 unrelated patients with AMD, indicating that sequence variations in CFHR5 do not play a major role in determining AMD susceptibility. However, our findings suggest a possible protective role for Asp169Asp. Further studies of different and larger populations of patient and control samples will be required to address this observation.

Show MeSH
Related in: MedlinePlus