Impaired ADAMTS9 secretion: A potential mechanism for eye defects in Peters Plus Syndrome.
Peters Plus syndrome (PPS), a congenital disorder of glycosylation, results from recessive mutations affecting the glucosyltransferase B3GLCT, leading to congenital corneal opacity and diverse extra-ocular manifestations. Together with the fucosyltransferase POFUT2, B3GLCT adds Glucoseβ1-3Fucose disaccharide to a consensus sequence in thrombospondin type 1 repeats (TSRs) of several proteins. Which of these target proteins is functionally compromised in PPS is unknown. We report here that haploinsufficiency of murine Adamts9, encoding a secreted metalloproteinase with 15 TSRs, leads to congenital corneal opacity and Peters anomaly (persistent lens-cornea adhesion), which is a hallmark of PPS. Mass spectrometry of recombinant ADAMTS9 showed that 9 of 12 TSRs with the O-fucosylation consensus sequence carried the Glucoseβ1-3Fucose disaccharide and B3GLCT knockdown reduced ADAMTS9 secretion in HEK293F cells. Together, the genetic and biochemical findings imply a dosage-dependent role for ADAMTS9 in ocular morphogenesis. Reduced secretion of ADAMTS9 in the absence of B3GLCT is proposed as a mechanism of Peters anomaly in PPS. The functional link between ADAMTS9 and B3GLCT established here also provides credence to their recently reported association with age-related macular degeneration.
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Johanne
J
Dubail
Department of Biochemistry and Cell Biology, Stony Brook University, NY 11794, USA.
Deepika
D
Vasudevan
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Lauren W
LW
Wang
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Sarah E
SE
Earp
Department of Pediatrics and Biomedical Engineering, Case Western Reserve University, 11000 Euclid Avenue, Cleveland, OH 44106, USA.
Michael W
MW
Jenkins
Department of Biochemistry and Cell Biology, Stony Brook University, NY 11794, USA.
Robert S
RS
Haltiwanger
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Suneel S
SS
Apte
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