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

Ulrike Schwarze, Wouter I. Schievink, Elizabeth Petty, Michael R. Jaff, Dusica Babovic-Vuksanovic, Kenneth J. Cherry, Melanie Pepin, Peter H. Byers

Research output: Contribution to journalArticle

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Abstract

Mutations in the COL3A1 gene that encodes the chains of type III procollagen 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 fibrillar collagen-gene mutations that lead to allele instability or failure to incorporate proof-chains into trimers - and that thus reduce the amount of mature molecules produced - result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Furthermore, mice heterozygous for Col3al "null" alleles have no identified phenotype. We have now found 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 transcribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutation, 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 truncated protein that was not incorporated into mature type III procollagen molecules. In all probands, the presenting feature was vascular aneurysm or rupture. Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those 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 structurally altered molecules into fibrils.

Original languageEnglish (US)
Pages (from-to)989-1001
Number of pages13
JournalAmerican Journal of Human Genetics
Volume69
Issue number5
DOIs
StatePublished - Jan 1 2001

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Ehlers-Danlos Syndrome
Haploinsufficiency
Collagen Type III
Blood Vessels
Alleles
Phenotype
Mutation
Nonsense Codon
Exons
Fibrillar Collagens
Genes
Dominant Genes
Protein Deficiency
Messenger RNA
Frameshift Mutation
Proteins
Point Mutation
Aneurysm
Rupture
Collagen

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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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. / Schwarze, Ulrike; Schievink, Wouter I.; Petty, Elizabeth; Jaff, Michael R.; Babovic-Vuksanovic, Dusica; Cherry, Kenneth J.; Pepin, Melanie; Byers, Peter H.

In: American Journal of Human Genetics, Vol. 69, No. 5, 01.01.2001, p. 989-1001.

Research output: Contribution to journalArticle

Schwarze, Ulrike ; Schievink, Wouter I. ; Petty, Elizabeth ; Jaff, Michael R. ; Babovic-Vuksanovic, Dusica ; Cherry, Kenneth J. ; Pepin, Melanie ; Byers, Peter H. / 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. In: American Journal of Human Genetics. 2001 ; Vol. 69, No. 5. pp. 989-1001.
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abstract = "Mutations in the COL3A1 gene that encodes the chains of type III procollagen 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 fibrillar collagen-gene mutations that lead to allele instability or failure to incorporate proof-chains into trimers - and that thus reduce the amount of mature molecules produced - result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Furthermore, mice heterozygous for Col3al {"}null{"} alleles have no identified phenotype. We have now found 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 transcribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutation, 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 truncated protein that was not incorporated into mature type III procollagen molecules. In all probands, the presenting feature was vascular aneurysm or rupture. Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which {"}null{"} mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those 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 structurally altered molecules into fibrils.",
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T1 - 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

AU - Schwarze, Ulrike

AU - Schievink, Wouter I.

AU - Petty, Elizabeth

AU - Jaff, Michael R.

AU - Babovic-Vuksanovic, Dusica

AU - Cherry, Kenneth J.

AU - Pepin, Melanie

AU - Byers, Peter H.

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AB - Mutations in the COL3A1 gene that encodes the chains of type III procollagen 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 fibrillar collagen-gene mutations that lead to allele instability or failure to incorporate proof-chains into trimers - and that thus reduce the amount of mature molecules produced - result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Furthermore, mice heterozygous for Col3al "null" alleles have no identified phenotype. We have now found 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 transcribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutation, 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 truncated protein that was not incorporated into mature type III procollagen molecules. In all probands, the presenting feature was vascular aneurysm or rupture. Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those 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 structurally altered molecules into fibrils.

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