title: Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa.
abstract: In patients with autosomal-recessive retinitis pigmentosa (arRP), homozygosity mapping was performed for detection of regions harboring genes that might be causative for RP. In one affected sib pair, a shared homozygous region of 5.0 Mb was identified on chromosome 6, within the RP25 locus. One of the genes residing in this interval was the retina-expressed gene EGFL11. Several genes resembling EGFL11 were predicted just centromeric of EGFL11. Extensive long-range RT-PCR, combined with 5'- and 3'- RACE analysis, resulted in the identification of a 10-kb transcript, starting with the annotated exons of EGFL11 and spanning 44 exons and 2 Mb of genomic DNA. The transcript is predicted to encode a 3165-aa extracellular protein containing 28 EGF-like and five laminin A G-like domains. Interestingly, the second part of the protein was found to be the human ortholog of Drosophila eyes shut (eys), also known as spacemaker, a protein essential for photoreceptor morphology. Mutation analysis in the sib pair homozygous at RP25 revealed a nonsense mutation (p.Tyr3156X) segregating with RP. The same mutation was identified homozygously in three arRP siblings of an unrelated family. A frame-shift mutation (pPro2238ProfsX16) was found in an isolated RP patient. In conclusion, we identified a gene, coined eyes shut homolog (EYS), consisting of EGFL11 and the human ortholog of Drosophila eys, which is mutated in patients with arRP. With a size of 2 Mb, it is one of the largest human genes, and it is by far the largest retinal dystrophy gene. The discovery of EYS might shed light on a critical component of photoreceptor morphogenesis.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, the Netherlands. r.collin@antrg.umcn.nl
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: Karin W
authors.initials: KW
authors.lastname: Littink
authors.forename: B Jeroen
authors.initials: BJ
authors.lastname: Klevering
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Marijke N
authors.initials: MN
authors.lastname: Zonneveld
authors.forename: Ellen A W
authors.initials: EA
authors.lastname: Blokland
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D004596:Electroretinography; D005091:Exons; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D035781:Siblings
chemical_list: D018389:Codon, Nonsense; D029721:Drosophila Proteins; C533105:EYS protein, human; D005136:Eye Proteins; D012333:RNA, Messenger; C514625:eys protein, Drosophila