Human Molecular Genetics Advance Access originally published online on August 4, 2009
Human Molecular Genetics 2009 18(20):3969-3977; doi:10.1093/hmg/ddp338
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Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma
1 National Institute of Genetic Engineering and Biotechnology, Tehran, Iran, 2 Department of Genetics, School of Basic Science, Tarbiat Modares University, Tehran, Iran, 3 Department of Biotechnology and 4 School of Biology, University College of Science, University of Tehran, Tehran, Iran, 5 Ophthalmic Research Center, Shahid Beheshti University MC, Tehran, Iran, 6 Department of Ophthalmology, Iran University of Medical Sciences, Hazrat Rasool Hospital, Tehran, Iran, 7 Illumina Inc, 9885 Towne Centre Drive, San Diego, CA 92121, USA, 8 Center of Excellence in Biomathematics, School of Mathematics, Statistics, and Computer Science, College of Science, University of Tehran, Tehran, Iran and 9 Department of Molecular Neuroscience and Reta Lila Weston Laboratories, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
* To whom correspondence should be addressed. Tel: +98 9122181251 (E.E.)/+44 2078373611 (C.P.R.); Fax: +98 2166405141 (E.E.)/+44 2078331016 (C.P.R.); Email: elaheelahi{at}ut.ac.ir (E.E.)/c.paisan-ruiz{at}ion.ucl.ac.uk (C.P.R.)
Received June 13, 2009; Accepted July 20, 2009
Glaucoma is a heterogeneous group of optic neuropathies that manifests by optic nerve head cupping or degeneration of the optic nerve, resulting in a specific pattern of visual field loss. Glaucoma leads to blindness if left untreated, and is considered the second leading cause of blindness worldwide. The subgroup primary congenital glaucoma (PCG) is characterized by an anatomical defect in the trabecular meshwork, and age at onset in the neonatal or infantile period. It is the most severe form of glaucoma. CYP1B1 was the first gene genetically linked to PCG, and CYP1B1 mutations are the cause of disease in 20–100% of patients in different populations. Here, we report that LTBP2 encoding latent transforming growth factor beta binding protein 2 is a PCG causing gene, confirming results recently reported. A disease-associated locus on chromosome 14 was identified by performing whole genome autozygosity mapping in Iranian PCG families using high density single nucleotide polymorphism chips, and two disease-segregating loss of function mutations in LTBP2, p.Ser472fsX3 and p.Tyr1793fsX55, were observed in two families while sequencing candidate genes in the locus. The p.Tyr1793fsX55 mutation affects an amino acid close to the C-terminal of the encoded protein. Subsequently, LTBP2 expression was shown in human eyes, including the trabecular meshwork and ciliary processes that are thought to be relevant to the etiology of PCG.
Present address: Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.