Null mutations in LTBP2 cause primary congenital glaucoma

M. Ali, M. Mckibbin, A. Booth, D.A. Parry, P. Jain, S.A. Riazuddin, J.F. Hejtmancik, S.N. Khan, S. Firasat, M. Shires, D.F. Gilmour, K. Towns, A.L. Murphy, Dimitar Azmanov, I. Tournev, S. Cherninkova, H. Jafri, Y. Raashid, C. Toomes, J. Craig & 4 others David Mackey, Luba Kalaydjieva, S. Riazuddin, C.F. Inglehearn

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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.
Original languageEnglish
Pages (from-to)664-671
JournalThe American Journal of Human Genetics
Volume84
DOIs
Publication statusPublished - 2009

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Glaucoma
Mutation
Genes
Roma
Anterior Eye Segment
Microfibrils
Ciliary Body
Extracellular Matrix Proteins
Pakistan
Anterior Chamber
Optic Nerve
Intraocular Pressure
Cell Adhesion
Transforming Growth Factor beta
Carrier Proteins
Chromosomes
Muscles

Cite this

Ali, M., Mckibbin, M., Booth, A., Parry, D. A., Jain, P., Riazuddin, S. A., ... Inglehearn, C. F. (2009). Null mutations in LTBP2 cause primary congenital glaucoma. The American Journal of Human Genetics, 84, 664-671. https://doi.org/10.1016/j.ajhg.2009.03.017
Ali, M. ; Mckibbin, M. ; Booth, A. ; Parry, D.A. ; Jain, P. ; Riazuddin, S.A. ; Hejtmancik, J.F. ; Khan, S.N. ; Firasat, S. ; Shires, M. ; Gilmour, D.F. ; Towns, K. ; Murphy, A.L. ; Azmanov, Dimitar ; Tournev, I. ; Cherninkova, S. ; Jafri, H. ; Raashid, Y. ; Toomes, C. ; Craig, J. ; Mackey, David ; Kalaydjieva, Luba ; Riazuddin, S. ; Inglehearn, C.F. / Null mutations in LTBP2 cause primary congenital glaucoma. In: The American Journal of Human Genetics. 2009 ; Vol. 84. pp. 664-671.
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title = "Null mutations in LTBP2 cause primary congenital glaucoma",
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.",
author = "M. Ali and M. Mckibbin and A. Booth and D.A. Parry and P. Jain and S.A. Riazuddin and J.F. Hejtmancik and S.N. Khan and S. Firasat and M. Shires and D.F. Gilmour and K. Towns and A.L. Murphy and Dimitar Azmanov and I. Tournev and S. Cherninkova and H. Jafri and Y. Raashid and C. Toomes and J. Craig and David Mackey and Luba Kalaydjieva and S. Riazuddin and C.F. Inglehearn",
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Ali, M, Mckibbin, M, Booth, A, Parry, DA, Jain, P, Riazuddin, SA, Hejtmancik, JF, Khan, SN, Firasat, S, Shires, M, Gilmour, DF, Towns, K, Murphy, AL, Azmanov, D, Tournev, I, Cherninkova, S, Jafri, H, Raashid, Y, Toomes, C, Craig, J, Mackey, D, Kalaydjieva, L, Riazuddin, S & Inglehearn, CF 2009, 'Null mutations in LTBP2 cause primary congenital glaucoma' The American Journal of Human Genetics, vol. 84, pp. 664-671. https://doi.org/10.1016/j.ajhg.2009.03.017

Null mutations in LTBP2 cause primary congenital glaucoma. / Ali, M.; Mckibbin, M.; Booth, A.; Parry, D.A.; Jain, P.; Riazuddin, S.A.; Hejtmancik, J.F.; Khan, S.N.; Firasat, S.; Shires, M.; Gilmour, D.F.; Towns, K.; Murphy, A.L.; Azmanov, Dimitar; Tournev, I.; Cherninkova, S.; Jafri, H.; Raashid, Y.; Toomes, C.; Craig, J.; Mackey, David; Kalaydjieva, Luba; Riazuddin, S.; Inglehearn, C.F.

In: The American Journal of Human Genetics, Vol. 84, 2009, p. 664-671.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Null mutations in LTBP2 cause primary congenital glaucoma

AU - Ali, M.

AU - Mckibbin, M.

AU - Booth, A.

AU - Parry, D.A.

AU - Jain, P.

AU - Riazuddin, S.A.

AU - Hejtmancik, J.F.

AU - Khan, S.N.

AU - Firasat, S.

AU - Shires, M.

AU - Gilmour, D.F.

AU - Towns, K.

AU - Murphy, A.L.

AU - Azmanov, Dimitar

AU - Tournev, I.

AU - Cherninkova, S.

AU - Jafri, H.

AU - Raashid, Y.

AU - Toomes, C.

AU - Craig, J.

AU - Mackey, David

AU - Kalaydjieva, Luba

AU - Riazuddin, S.

AU - Inglehearn, C.F.

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2009.03.017

DO - 10.1016/j.ajhg.2009.03.017

M3 - Article

VL - 84

SP - 664

EP - 671

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

SN - 0002-9297

ER -