title: Identification and molecular characterisation of a homozygous missense mutation in the ADAMTS10 gene in a patient with Weill-Marchesani syndrome.
abstract: Weill-Marchesani syndrome is a rare disorder of the connective tissue. Functional variants in ADAMTS10 are associated with Weill-Marchesani syndrome-1. We identified a homozygous missense mutation, c.41T>A, of the ADAMTS10 gene in a 19-year-old female with typical symptoms of WMS1: proportionate short stature, brachydactyly, joint stiffness, and microspherophakia. The ADAMTS10 missense mutation was analysed in silico, with conflicting results as to its effects on protein function, but it was predicted to affect the leader sequence. Molecular characterisation in HEK293 Ebna cells revealed an intracellular mis-targeting of the ADAMTS10 protein with a reduced concentration of the polypeptide in the endoplasmic reticulum. A large reduction in glycosylation of the cytoplasmic fraction of the mutant ADAMTS10 protein versus the wild-type protein and a lack of secretion of the mutant protein are also evident in our results.In conclusion, we identified a novel missense mutation of the ADAMTS10 gene and confirmed the functional consequences suggested by the in silico analysis by conducting molecular studies.
authors.affiliation: Department of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Hannes
authors.identifier: 0000000244386043
authors.initials: H
authors.lastname: Steinkellner
authors.affiliation: Department of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Etzler
authors.affiliation: Department of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Laura
authors.initials: L
authors.lastname: Gogoll
authors.affiliation: Department of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Neesen
authors.affiliation: Department of Ophthalmology, Medical University of Vienna, Vienna, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Stifter
authors.affiliation: Department of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brandau
authors.affiliation: Department of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Franco
authors.initials: F
authors.lastname: Laccone
mesh_terms: D005260:Female; D006801:Humans; D055815:Young Adult; D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071096:ADAMTS Proteins; D000595:Amino Acid Sequence; D001483:Base Sequence; D003198:Computer Simulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression; D005838:Genotype; D006031:Glycosylation; D057809:HEK293 Cells; D006720:Homozygote; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D021381:Protein Transport; D017422:Sequence Analysis, DNA; D056846:Weill-Marchesani Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C494614:ADAMTS10 protein, human