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PMID: 18976725 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa.

American journal of human genetics ·Vol. 83 ·No. 5 ·2008-11-00 ·Pages 594-603

Collin RW, Littink KW, Klevering BJ, van den Born LI, Koenekoop RK, Zonneveld MN, Blokland EA, Strom TM, Hoyng CB, den Hollander AI, Cremers FP

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.

MeSH Terms
Amino Acid Sequence Amino Acid Substitution Animals Case-Control Studies Chromosome Mapping Chromosomes, Human, Pair 6 Codon, Nonsense DNA Mutational Analysis Drosophila/genetics Drosophila Proteins/genetics Electroretinography Exons Eye Proteins/genetics Female Frameshift Mutation Genes, Recessive Homozygote Humans Male Molecular Sequence Data Mutation Pedigree Polymorphism, Single Nucleotide Protein Structure, Tertiary RNA, Messenger/metabolism Retinitis Pigmentosa/genetics Sequence Homology, Amino Acid Siblings
Chemicals
Codon, Nonsense Drosophila Proteins EYS protein, human Eye Proteins RNA, Messenger eys protein, Drosophila
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Collin Rob W J
Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, the Netherlands. [email protected]
Littink Karin W
Klevering B Jeroen
van den Born L Ingeborgh
Koenekoop Robert K
Zonneveld Marijke N
Blokland Ellen A W
Strom Tim M
Hoyng Carel B
den Hollander Anneke I
Cremers Frans P M
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1016/j.ajhg.2008.10.014
Email
[email protected]
Published
2008-11-00
Epub
2008-00-30
Pages
594-603
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC2668042
Subset
IM
External Links
PubMed source DOI: 10.1016/j.ajhg.2008.10.014 PMC Full Text View journal details
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