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.
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin.
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin.
- Published Article
Wiley (John Wiley & Sons)
- Publication Date
Nov 01, 2017
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.
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This record was last updated on 06/09/2018 and may not reflect the most current and accurate biomedical/scientific data available from NLM.
The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/28722276