COL2A1 – Platyspondylic Lethal Skeletal Dysplasia Torrance Type

COL2A1 encodes the α1 chain of type II collagen, a major structural component of cartilage. Platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T) is a severe chondrodysplasia characterized by extreme short stature, platyspondyly, pelvic hypoplasia and brachydactyly. Heterozygous mutations in the C-propeptide region of COL2A1 disrupt normal cartilage matrix assembly and lead to lethal skeletal defects.

Genetic evidence arises from a fetus diagnosed prenatally with PLSD-T carrying a novel in-frame deletion, c.4458_4460del (p.Phe1486del), in COL2A1, confirming the clinical diagnosis; the mother exhibited mild spondyloperipheral dysplasia due to somatic mosaicism for the same variant (1 proband; [PMID:22495950]). Segregation in this single family supports a semidominant mode of inheritance with variable expressivity.

In 2011, an ENU-induced mouse model carrying a homologous C-propeptide missense mutation, c.44406>C (p.Asp1469Ala), recapitulated PLSD-T features: heterozygotes were small, homozygotes died perinatally with severe limb shortening, spinal dysplasia and pelvic hypoplasia. Mutant collagen was retained in the ER, triggering stress responses and impaired secretion ([PMID:21538020]).

Further functional studies in a separate Col2a1 mutant mouse bearing p.Tyr1391Ser demonstrated severe ER expansion, upregulation of ER stress markers (Grp94, Chop) and apoptosis of growth plate chondrocytes in homozygotes, mirroring human PLSD-T pathology ([PMID:26545783]). These data establish ER stress-mediated apoptosis as a key pathogenic mechanism.

Together, these observations integrate human genetic, animal modeling and cellular studies to define a clear mechanistic link: C-propeptide mutations in COL2A1 cause intracellular collagen retention, ER stress and chondrocyte apoptosis, resulting in the lethal skeletal dysplasia phenotype of PLSD-T. This association meets ClinGen criteria for a moderate level of clinical validity.

Key take-home: COL2A1 C-propeptide mutations should be included in diagnostic gene panels for lethal skeletal dysplasias and warrant genetic counseling for recurrence risk.

References

• American journal of medical genetics. Part A • 2012 • Spondyloperipheral dysplasia as the mosaic form of platyspondylic lethal skeletal dysplasia Torrance type in mother and fetus with the same COL2A1 mutation. PMID:22495950
• Mammalian genome • 2011 • ENU-induced missense mutation in the C-propeptide coding region of Col2a1 creates a mouse model of platyspondylic lethal skeletal dysplasia, Torrance type. PMID:21538020
• Biochemical and biophysical research communications • 2015 • Endoplasmic reticulum stress-mediated apoptosis contributes to a skeletal dysplasia resembling platyspondylic lethal skeletal dysplasia, Torrance type, in a novel Col2a1 mutant mouse line. PMID:26545783

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