title: Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies.
abstract: Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen.
authors.affiliation: Division of Molecular Pediatrics, CHUV, Lausanne, Switzerland. andreas.zankl@hospvd.ch
authors.forename: Andreas
authors.initials: A
authors.lastname: Zankl
authors.forename: Luitgard
authors.initials: L
authors.lastname: Neumann
authors.forename: Jaako
authors.initials: J
authors.lastname: Ignatius
authors.forename: Peter
authors.initials: P
authors.lastname: Nikkels
authors.forename: Connie
authors.initials: C
authors.lastname: Schrander-Stumpel
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.forename: Katja
authors.initials: K
authors.lastname: Hilbert
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Juergen
authors.initials: J
authors.lastname: Spranger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D002675:Child, Preschool; D024043:Collagen Type II / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005313:Fetal Death; D005500:Follow-Up Studies; D005532:Foot Deformities, Congenital / Q000473:pathology; D006228:Hand Deformities, Congenital / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009139:Musculoskeletal Abnormalities; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology; D010641:Phenotype
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II