Null Mutations in LTBP2 Cause Primary Congenital Glaucoma
Null Mutations in LTBP2 Cause Primary Congenital Glaucoma
复制标题
DOI：
10.1016/j.ajhg.2009.03.017
复制
发表时间：
2009-05-15
影响因子：
9.8
通讯作者：
Inglehearn, Chris F.
中科院分区：
文献类型：
--
作者：
Ali, Manir;McKibbin, Martin;Inglehearn, Chris F.
原发性先天性青光眼（PCG）是一种常染色体隐性疾病，其特征是高眼内压（IOP），通常发生在生命的第一年内，这可能会导致视神经损伤、地球仪增大和永久性视力丧失。到目前为止，PCG已经与三个位点连锁：2 p21（GLC 3A），其负责基因是CYP 1B 1，1 p36（GLC 3B）和14 q24（GLC 3C），其基因仍有待鉴定。在这里，我们报告LTBP 2无效突变导致PCG在四个来自巴基斯坦的血缘家庭和吉普赛民族的患者。LTBP 2定位于染色体14q24.3，但在记录的GLC 3C基因座附近约1.3 Mb。因此，还有待确定LTBP 2是否是GLC 3C基因，或者第二个相邻基因是否也与PCG有关。LTBP 2是潜伏性转化生长因子（transforming growth factor，TGF）-β结合蛋白家族中最大的成员，是一种具有多结构域结构的细胞外基质蛋白。它与原纤维蛋白具有同源性，可能在细胞粘附中起作用，并作为微纤维的结构组分。我们证实了LTBP 2在眼前段、睫状体、特别是睫状突中的定位。这些发现揭示了LTBP 2对于眼睛前房的正常发育是必不可少的，其中它可能在维持睫状肌张力方面具有结构性作用。
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.