Null mutations in LTBP2 cause primary congenital glaucoma.
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.
Ali
Manir
M
Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK. medma@leeds.ac.uk
McKibbin
Martin
M
Booth
Adam
A
Parry
David A
DA
Jain
Payal
P
Riazuddin
S Amer
SA
Hejtmancik
J Fielding
JF
Khan
Shaheen N
SN
Firasat
Sabika
S
Shires
Mike
M
Gilmour
David F
DF
Towns
Katherine
K
Murphy
Anna-Louise
AL
Azmanov
Dimitar
D
Tournev
Ivailo
I
Cherninkova
Sylvia
S
Jafri
Hussain
H
Raashid
Yasmin
Y
Toomes
Carmel
C
Craig
Jamie
J
Mackey
David A
DA
Kalaydjieva
Luba
L
Riazuddin
Sheikh
S
Inglehearn
Chris F
CF
D002874:Chromosome Mapping; D002924:Ciliary Body / Q000378:metabolism*; D003241:Consanguinity; D005901:Glaucoma / Q000151:congenital / Q000235:genetics*; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree
C509035:LTBP2 protein, human; D053779:Latent TGF-beta Binding Proteins