Table 6.

Autosomal Dominant Multiple Epiphyseal Dysplasia: Mechanism of Disease Causation

Gene 1Special Consideration
COL9A1 In-frame exon-skipping COL9 pathogenic variants result in deletion of amino acids from the COL3 domain, which may affect its ability to fold correctly or interact w/other components of the cartilage ECM [Fresquet et al 2007].
COL9A2
COL9A3
COMP Pathogenic variants in the type III repeats result in misfolding of the protein & its retention in the rER of chondrocytes, causing reduced chondrocyte proliferation & increased/dysregulated cell death [Suleman et al 2012]. The effect of pathogenic variants in the C-terminal domain is not fully resolved, but these do not always prevent the secretion of abnormal protein [Piróg-Garcia et al 2007].
MATN3 MATN3 pathogenic variants delay protein folding, which elicits an unfolded protein response & results in the retention of abnormal matrilin-3 in the rER.

ECM = extracellular matrix; rER = rough endoplasmic reticulum

1.

Genes from Table 1 in alphabetic order.

From: Multiple Epiphyseal Dysplasia, Autosomal Dominant

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