Affordable Access

deepdyve-link
Publisher Website

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.

Authors
  • Hendee, Kathryn1
  • Wang, Lauren Weiping2
  • Reis, Linda M3
  • Rice, Gregory M4
  • Apte, Suneel S2
  • Semina, Elena V1, 3, 5
  • 1 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 2 Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
  • 3 Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 4 Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • 5 Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 01, 2017
Volume
38
Issue
11
Pages
1485–1490
Identifiers
DOI: 10.1002/humu.23299
PMID: 28722276
Source
Medline
Keywords
License
Unknown

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.

Report this publication

Statistics

Seen <100 times