title: Gene Structure of the 10q26 Locus: A Clue to Cracking the ARMS2/HTRA1 Riddle?
abstract: Age-related macular degeneration (AMD) is a sight-threatening disorder of the central retina. Being the leading cause of visual impairment in senior citizens, it represents a major public health issue in developed countries. Genetic studies of AMD identified two major susceptibility loci on chromosomes 1 and 10. The high-risk allele of the 10q26 locus encompasses three genes, PLEKHA1, ARMS2, and HTRA1 with high linkage disequilibrium and the individual contribution of the encoded proteins to disease etiology remains controversial. While PLEKHA1 and HTRA1 are highly conserved proteins, ARMS2 is only present in primates and can be detected by using RT-PCR. On the other hand, there is no unequivocal evidence for the existence of the encoded protein. However, it has been reported that risk haplotypes only affect the expression of ARMS2 (but not of HTRA1), making ARMS2 the best candidate for being the genuine AMD gene within this locus. Yet, homozygous carriers of a common haplotype carry a premature stop codon in the ARMS2 gene (R38X) and therefore lack ARMS2, but this variant is not associated with AMD. In this work we aimed at characterizing the diversity of transcripts originating from this locus, in order to find new hints on how to resolve this perplexing paradox. We found chimeric transcripts originating from the PLEKHA1 gene but ending in ARMS2. This finding may give a new explanation as to how variants in this locus contribute to AMD.
authors.affiliation: Division of Experimental Ophthalmology, University of Tuebingen, Roentgenweg 11, 72076, Tuebingen, Germany. eloed.koertvely@uni-tuebingen.de.
authors.forename: Elod
authors.initials: E
authors.lastname: Kortvely
authors.affiliation: Division of Experimental Ophthalmology, University of Tuebingen, Roentgenweg 11, 72076, Tuebingen, Germany. marius.ueffing@uni-tuebingen.de.
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D018389:Codon, Nonsense; D015870:Gene Expression; D023061:Gene Order; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010802:Phylogeny; D011506:Proteins / Q000145:classification / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: C514392:ARMS2 protein, human; D018389:Codon, Nonsense; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C435927:PLEKHA1 protein, human; D011506:Proteins; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases
keywords: ARMS2; Age-related macular degeneration; Alternative splicing; Chimeric transcripts; Gene transcription; HTRA1; PLEKHA1; rs10490924; rs11200638; rs2736911