Contribution of the latent transforming growth factor-ß binding protein 2 gene to etiology of primary open angle glaucoma and pseudoexfoliation syndrome.

PURPOSE: To assess for the first time the possible contribution of latent transforming growth factor (TGF)-beta binding protein 2 (LTBP2), an extracellular matrix (ECM) protein that associates with fibrillin-1-containing microfibrils, to the etiology of primary open angle glaucoma (POAG) and pseudoexfoliation (PEX) syndrome. Mutations in LTBP2 have previously been shown to be the cause of primary congenital glaucoma (PCG) and other disorders that often manifest as secondary glaucoma. METHODS: All exons of LTBP2 were sequenced in the DNA of 42 unrelated patients with POAG and 48 unrelated patients with PEX syndrome. Contribution of candidate variations to disease was assessed by screening in control individuals and use of biochemical, bioinformatics, and evolutionary criteria, and in one case by segregation analysis within the family of a proband with POAG. Microscopy was performed on the skin of a patient with PEX syndrome whose condition developed into PEX glaucoma during the course of the study and on the skin of her son previously identified with PCG who harbored the same LTBP2 mutation. RESULTS: Among the 30 sequence variations observed in LTBP2, five found in five patients with POAG and two found in two patients with PEX glaucoma syndrome may contribute to their diseases. One of the mutations was observed in a patient with POAG and in a patient with PEX glaucoma syndrome. Light, fluorescent, and electron microscopy showed that a mutation present in one of the individuals affected with PEX glaucoma syndrome and in her son affected with PCG causes disruptions in the ECM. CONCLUSIONS: Some LTBP2 sequence variations can contribute to the etiology of POAG and PEX glaucoma syndrome. It is not expected that in these diseases LTBP2 mutations behave in a strictly Mendelian fashion with complete penetrance. In conjunction with recent findings, the results suggest that anomalies in the ECM are among the factors that can contribute to POAG and PEX glaucoma syndrome. LTBP2 and other related ECM protein coding genes should be screened in larger cohorts with these diseases, which are common disorders and important to the public health.

LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix.

Latent transforming growth factor (TGF) beta-binding protein 2 (LTBP2) is an extracellular matrix (ECM) protein that associates with fibrillin-1 containing microfibrils. Various factors prompted considering LTBP2 in the etiology of isolated ectopia lentis and associated conditions such as Weill-Marchesani syndrome (WMS) and Marfan syndrome (MFS). LTBP2 was screened in 30 unrelated Iranian patients. Mutations were found only in one WMS proband and one MFS proband. Homozygous c.3529G>A (p.Val1177Met) was shown to cause autosomal recessive WMS or WM-like syndrome by several approaches, including homozygosity mapping. Light, fluorescent, and electron microscopy evidenced disruptions of the microfibrillar network in the ECM of the proband's skin. In conjunction with recent findings regarding other ECM proteins, the results presented strongly support the contention that anomalies in WMS patients are due to disruptions in the ECM. Heterozygous c.1642C >T (p.Arg548*) possibly contributed to MFS-related phenotypes, including ocular manifestations, mitral valve prolapse, and pectus excavatum, but was not cause of MFS.