Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.
Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm's canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.
Tomokazu
T
Souma
Stuart W
SW
Tompson
Benjamin R
BR
Thomson
Owen M
OM
Siggs
Krishnakumar
K
Kizhatil
Shinji
S
Yamaguchi
Liang
L
Feng
Vachiranee
V
Limviphuvadh
Kristina N
KN
Whisenhunt
Sebastian
S
Maurer-Stroh
Tammy L
TL
Yanovitch
Luba
L
Kalaydjieva
Dimitar N
DN
Azmanov
Simone
S
Finzi
Lucia
L
Mauri
Shahrbanou
S
Javadiyan
Emmanuelle
E
Souzeau
Tiger
T
Zhou
Alex W
AW
Hewitt
Bethany
B
Kloss
Kathryn P
KP
Burdon
David A
DA
Mackey
Keri F
KF
Allen
Jonathan B
JB
Ruddle
Sing-Hui
SH
Lim
Steve
S
Rozen
Khanh-Nhat
KN
Tran-Viet
Xiaorong
X
Liu
Simon
S
John
Janey L
JL
Wiggs
Francesca
F
Pasutto
Jamie E
JE
Craig
Jing
J
Jin
Susan E
SE
Quaggin
Terri L
TL
Young
D042682:Angiopoietins / Q000378:metabolism; D000818:Animals; D059472:Exome; D005192:Family Health; D018628:Gene Dosage; D005786:Gene Expression Regulation; D005901:Glaucoma / Q000151:congenital* / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010766:Phosphorylation; D042787:Receptor, TIE-2 / Q000235:genetics*; D015398:Signal Transduction; D014129:Trabecular Meshwork
D042682:Angiopoietins; D008024:Ligands; D042787:Receptor, TIE-2; C079086:Tek protein, mouse