Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV

Mutations in the COL3A1 gene that encodes the chains of type III procollage n result in the vascular form of Ehlers-Danlos syndrome (EDS), EDS type IV, if they alter the sequence in the triple-helical domain. Although other fi brillar collagen-gene mutations that lead to allele instability or failure to incorporate pro alpha -chains into trimers-and that thus reduce the amou nt of mature molecules produced-result in clinically apparent phenotypes, n o such mutations have been identified in COL3A1. Furthermore, mice heterozy gous for Col3a1 "null" alleles have no identified phenotype. We have now fo und three frameshift mutations (1832delAA, 413delC, and 555delT) that lead to premature termination codons (PTCs) in exons 27, 6, and 9, respectively, and to allele-product instability. The mRNA from each mutant allele was tr anscribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutati on, in the final exon, that resulted in a PTC (4294C -->T [Arg1432Ter]). In this last instance, the mRNA was stable but led to synthesis of a truncate d protein that was not incorporated into mature type III procollagen molecu les. In all probands, the presenting feature was vascular aneurysm or ruptu re. Thus, in contrast to mutations in genes that encode the dominant protei n of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result i n phenotypes milder than those caused by mutations that alter protein seque nce, the phenotypes produced by these mutations in COL3A1 overlap with thos e of the vascular form of EDS. This suggests that the major effect of many of these dominant mutations in the "minor" collagen genes may be expressed through protein deficiency rather than through incorporation of structurall y altered molecules into fibrils.