High myopia caused by a mutation in LEPREL1, encoding prolyl 3-hydroxylase 2 |
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| Authors: | Mordechai Shikma Gradstein Libe Pasanen Annika Ofir Rivka El Amour Khalil Levy Jaime Belfair Nadav Lifshitz Tova Joshua Sara Narkis Ginat Elbedour Khalil Myllyharju Johanna Birk Ohad S |
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| Affiliation: | 1The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev, Ben Gurion University of the Negev, Beer-Sheva 84105, Israel;2Department of Ophthalmology, Soroka Medical Center and Clalit Health Services, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel;3Biocenter Oulu, University of Oulu, FIN-90014, Oulu 90014, Finland;4Oulu Centre for Cell-Matrix Research, Department of Medical Biochemistry and Molecular Biology, University of Oulu, FIN-90014, Oulu 90014, Finland;5Genetics Institute, Soroka Medical Center, Beer-Sheva 84101, Israel |
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| Abstract: | Autosomal-recessive high-grade axial myopia was diagnosed in Bedouin Israeli consanguineous kindred. Some affected individuals also had variable expressivity of early-onset cataracts, peripheral vitreo-retinal degeneration, and secondary sight loss due to severe retinal detachments. Through genome-wide linkage analysis, the disease-associated gene was mapped to ～1.7 Mb on chromosome 3q28 (the maximum LOD score was 11.5 at θ = 0 for marker D3S1314). Sequencing of the entire coding regions and intron-exon boundaries of the six genes within the defined locus identified a single mutation (c.1523G>T) in exon 10 of LEPREL1, encoding prolyl 3-hydroxylase 2 (P3H2), a 2-oxoglutarate-dependent dioxygenase that hydroxylates collagens. The mutation affects a glycine that is conserved within P3H isozymes. Analysis of wild-type and p.Gly508Val (c.1523G>T) mutant recombinant P3H2 polypeptides expressed in insect cells showed that the mutation led to complete inactivation of P3H2. |
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