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

摘要

Abstract 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.