ScreeningADAMTS10in Dog Populations Supports Gly661Arg as the Glaucoma-Causing Variant in Beagles

Abstract

These findings support the Gly661Arg mutation of ADAMTS10 as the likely cause of POAG in beagles.

The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure

“…25 A mutation in ADAMTS10 has been reported as likely causative for glaucoma in a canine model of hereditary primary open-angle glaucoma. 1,71 ADAMTS10 is a secreted matrix metalloproteinase that can cleave fibrillin-1. 72,73 Although its exact function is not known, a role for ADAMTS10 in microfibril structure and function was first suggested by the finding that Weill-Marchesani syndrome can be caused either by recessive ADAMTS10 mutations 74 or dominant mutations in FBN1.…”

Genetics of Canine Primary Glaucomas

“…17,18,20 A Gly661Arg missense mutation (the amino acid glycine has been replaced by arginine at position 661) in ADAMTS10 was identified by a family-based mapping approach as the probable cause of beagle POAG. 76 ADAMTS10 is strongly expressed in the trabecular meshwork, supporting its role in aqueous humor outflow. 76 However, the molecular and cellular disease mechanisms leading from the ADAMTS10 missense mutation to plaque formation and increased aqueous humor outflow resistance within the trabecular meshwork still need to be determined.…”

“…76 ADAMTS10 is strongly expressed in the trabecular meshwork, supporting its role in aqueous humor outflow. 76 However, the molecular and cellular disease mechanisms leading from the ADAMTS10 missense mutation to plaque formation and increased aqueous humor outflow resistance within the trabecular meshwork still need to be determined. 24,67 The discovery of ADAMTS10 as a POAG gene in the beagle resulted in the microfibril hypothesis of glaucoma.…”

“…[65][66][67][68] Abnormalities in the ECM and the biomechanics of the optic nerve head's lamina cribrosa and the sclera also contribute to greater susceptibility of retinal ganglion cells to variations in IOP. [69][70][71][72][73][74][75] The recent discoveries of ADAMTS10 mutations responsible for POAG in beagles and Norwegian elkhounds, 25,76 as well as a mutation in ADAMTS17 causing canine PLL in many breeds, 29,77 and ongoing studies of canine POAG by the authors and others, 8,10 revealed that many forms of primary canine glaucoma are closely related to a group of connective tissue disorders resulting from abnormal microfibril formation. These so-called microfibrillopathies include Weill-Marchesani syndrome (WMS) and Marfan syndrome (MS) and are caused by mutations in genes responsible for normal microfibril formation, most importantly ADAMTS10, ADAMTS17, and fibrillin-1 (FBN1), resulting in defective microfibrils.…”

“…3 The study on canine POAG genetics was facilitated by (1) the availability of a well-established POAG beagle colony, and (2) the monogenic, autosomal-recessive inheritance of all investigated forms of canine POAG. 3,25,76,167 The disease is characterized by the gradual bilateral increase in aqueous humor outflow resistance and IOP over months or years despite normal-appearing ICA and pectinate ligament. 3 In contrast to PACG, vision loss occurs more slowly, and there is no apparent sex predisposition.…”