title: In-depth analysis of hyaline fibromatosis syndrome frameshift mutations at the same site reveal the necessity of personalized therapy.
abstract: Hyaline fibromatosis syndrome is an autosomal recessive disease caused by mutations in ANTXR2, a gene involved in extracellular matrix homeostasis. Sixty percent of patients carry frameshift mutations at a mutational hotspot in exon 13. We show in patient cells that these mutations lead to low ANTXR2 mRNA and undetectable protein levels. Ectopic expression of the proteins encoded by the mutated genes reveals that a two base insertion leads to the synthesis of a protein that is rapidly targeted to the ER-associated degradation pathway due to the modified structure of the cytosolic tail, which instead of being hydrophilic and highly disordered as in wild type ANTXR2, is folded and exposes hydrophobic patches. In contrast, one base insertion leads to a truncated protein that properly localizes to the plasma membrane and retains partial function. We next show that targeting the nonsense mediated mRNA decay pathway in patient cells leads to a rescue of ANTXR2 protein in patients carrying one base insertion but not in those carrying two base insertions. This study highlights the importance of in-depth analysis of the molecular consequences of specific patient mutations, which even when they occur at the same site can have drastically different consequences.
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Shixu E
authors.initials: SE
authors.lastname: Yan
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemmin
authors.forename: Suzanne
authors.initials: S
authors.lastname: Salvi
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Dariusz
authors.initials: D
authors.lastname: Rokicki
authors.forename: Matteo
authors.initials: M
authors.lastname: Dal Peraro
authors.forename: F Gisou
authors.initials: FG
authors.lastname: van der Goot
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D016368:Frameshift Mutation; D006367:HeLa Cells; D006801:Humans; D057770:Hyaline Fibromatosis Syndrome / Q000235:genetics* / Q000628:therapy*; D007223:Infant; D008958:Models, Molecular; D008969:Molecular Sequence Data; D059365:Nonsense Mediated mRNA Decay / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics*
chemical_list: C447150:ANTXR2 protein, human; D012333:RNA, Messenger; D018000:Receptors, Peptide