Clinical, structural, biochemical and X‐ray crystallographic correlates of pathogenicity for variants in the C‐propeptide region of the COL3A1 gene

Abstract

Vascular Ehlers-Danlos syndrome (vEDS) is a heritable disorder of connective tissue caused by pathological variants in the COL3A1 gene, which encodes the α1 chain of type III collagen. Type III collagen is a major component of skin, arterial walls, and the gastrointestinal tract. Collagen III protein deficiency manifests as an increased risk of rupture, perforation, and dissection of these structures. The most disruptive gene variants affect the collagen helix via glycine substitutions or splice donor site mutations. The C-propeptide region of COL3A1 includes exons 49-52 and has a crucial role in initiating the C-terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen COL3A1 variants have previously been reported in these exons, of which four were associated with a severe vEDS phenotype. We identified two novel C-propeptide missense variants; p.Pro1440Leu, p.Arg1432Leu, and a non-stop mutation, c.4400A > T, p. (*1467Leuext*45). These variants produce variable phenotypes ranging from obvious acrogeria to classical or hypermobile EDS. A previously reported variant p.Lys1313Arg is of unknown clinical significance but likely benign, based on this study. Assigning disease pathogenicity remains complex, clinical phenotyping and crystal structure evidence being crucial. We briefly compare reported phenotypes for patients with missense variants in the C-propeptide domain for other human collagen disorders including COL1A1 and COL1A2 (osteogenesis imperfecta).

Targeted next-generation sequencing makes new molecular diagnoses and expands genotype–phenotype relationship in Ehlers–Danlos syndrome

“…[18] However, collagen microscopy and biochemistry were normal in the patient, neither the patient nor her sister, who also carried the variant, had features of vascular EDS and structural studies indicated that the variant was unlikely to impair C-propeptide-mediated helical winding. [29,30] Consistent with previous reports, we observed significant phenotypic overlap between our EDS diagnostic categories and other HDCT as well as overlap amongst patients with pathogenic variants in individual causative genes. [2,3,6,19,20,22,23] genetic counseling for such patients should include the fact that the true significance of the variant will not be known until these additional tests are complete.…”

The collαgen III fibril has a “flexi-rod” structure of flexible sequences interspersed with rigid bioactive domains including two with hemostatic roles

“…Counterintuitively, most of the few disease-causing variants in the C-propeptide do not affect residues in identifiable structural or functional motifs (S2 Table). However, amino acid substitutions, for example, at propeptide positions 92, 211 or 219, might disrupt the three-dimensional structure [89] but their pathogenicity is still unproven. Thus, substitutions at some residues in the C-propeptide may result in EDS, some in perinatal lethality, and others in a minimal or undetectable phenotype.…”

Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers–Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility

“…12,13,28,29 However, to our knowledge, this is the first description of a similar overlapping phenotype in individuals with COL3A1 variants, specifically Glu>Lys substitutions. One individual with hyperextensible skin has previously been reported in the literature 30 with a COL3A1 variant that is not a Glu>Lys substitution (arginine to leucine in C-propeptide region) although the pathogenicity has not been confirmed.…”