Faculty Collaboration Database

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. Hum Mutat 2017 Nov;38(11):1485-1490

Date

07/20/2017

Pubmed ID

28722276

Pubmed Central ID

PMC5638704

DOI

10.1002/humu.23299

Scopus ID

2-s2.0-85026544662 (requires institutional sign-in at Scopus site)   25 Citations

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.

Author List

Hendee K, Wang LW, Reis LM, Rice GM, Apte SS, Semina EV

Authors

Kathryn Hendee in the CTSI department at Medical College of Wisconsin - CTSI
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ADAMTS Proteins
Child
Craniofacial Abnormalities
DNA Copy Number Variations
Diagnostic Imaging
Extracellular Matrix Proteins
Female
Genetic Association Studies
Glaucoma
Humans
Male
Mutation
Pedigree
Phenotype
Sequence Analysis, DNA