advertisement

Abstract #73485 Published in IGR 18-4

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; co-segregation 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 co-transfected wild-type ADAMTSL1 suggesting a dominant negative effect for this mutation. These data imply a multi-system role for ADAMTSL1 and present the first disease-associated variant affecting a C-mannosylation motif. This article is protected by copyright. All rights reserved.

Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.

Classification:

• ← Previous
• Next →