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.