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Published on: August 15, 2019
Null mutations in LTBP2 cause primary congenital glaucoma
Manir Ali1, Martin McKibbin, Adam Booth
1Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK. medma@leeds.ac.uk
Insights
Null mutations in the LTBP2 gene cause primary congenital glaucoma (PCG), an inherited eye condition leading to vision loss. This discovery identifies a new genetic cause for PCG, crucial for understanding and diagnosing this severe condition.
Area of Science:
- Ophthalmology
- Genetics
- Developmental Biology
Background:
- Primary congenital glaucoma (PCG) is an inherited condition causing high intraocular pressure in infants, potentially leading to irreversible vision loss.
- PCG is typically autosomal-recessive and has been genetically mapped to three loci (GLC3A, GLC3B, GLC3C), with only GLC3A's gene (CYP1B1) identified.
- The genetic basis for GLC3B and GLC3C remained elusive, hindering diagnosis and understanding of PCG pathogenesis.
Purpose of the Study:
- To identify the gene responsible for primary congenital glaucoma (PCG) in families where known genes were excluded.
- To investigate the role of LTBP2 in the etiology of PCG.
- To understand the function of LTBP2 in ocular development.
Main Methods:
- Genetic analysis of consanguineous families with PCG.
- Mutation screening of the LTBP2 gene.
- Gene mapping of LTBP2 to chromosome 14q24.3.
- Immunohistochemical analysis to determine LTBP2 localization in ocular tissues.
Main Results:
- Null mutations in LTBP2 were identified as a cause of PCG in Pakistani and Gypsy ethnic groups.
- LTBP2 was mapped to chromosome 14q24.3, proximal to the GLC3C locus.
- LTBP2 protein was localized to the anterior segment of the eye, specifically the ciliary body and ciliary processes.
Conclusions:
- LTBP2 mutations are a significant cause of primary congenital glaucoma.
- LTBP2 plays a critical role in the normal development of the anterior chamber of the eye.
- LTBP2 may function structurally in maintaining ciliary muscle tone, impacting intraocular pressure regulation.
Abstract:
Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone.
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