Identification and functional analysis of an ADAMTSL1 variant associated with a complex phenotype including congenital glaucoma, craniofacial, and other systemic features in a three-generation human pedigree

Developmental glaucoma can occur as an isolated or syndromic condition and is genetically heterogeneous. We describe a three-generation family affected with developmental glaucoma, myopia, and/or retinal defects associated with variable craniofacial/dental, auditory, brain, renal, and limb anomalies. Whole-exome sequencing identified a heterozygous c.124T>C, p.(Trp42Arg) allele in ADAMTSL1; cosegregation analysis confirmed the presence of this allele in four affected family members. The mutation affects a highly conserved residue and is strongly predicted to have a deleterious effect on protein function. Trp42 is normally modified by protein C-mannosylation, an unusual post-translational modification. Comparison of ADAMTSL1-WT (also known as punctin-1) and ADAMTSL1-p.Trp42Arg in vitro demonstrated that the latter was not secreted from transfected cells but retained intracellularly. Moreover, ADAMTSL1-p.Trp42Arg reduced secretion of cotransfected wild-type ADAMTSL1, suggesting a dominant negative effect for this mutation. These data imply a multisystem role for ADAMTSL1 and present the first disease-associated variant affecting a C-mannosylation motif.