Tags

Type your tag names separated by a space and hit enter

Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood.
Hum Mutat. 2007 Apr; 28(4):387-95.HM

Abstract

Mutations in the COL1A1 and COL1A2 genes, encoding the proalpha1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers-Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly-Xaa-Yaa repeat, few nonglycine substitutions have been reported. Two arginine-to-cysteine substitutions in the alpha1(I)-collagen chain are associated with classic EDS [R134C (p.R312C)] or autosomal dominant Caffey disease with mild EDS features [R836C (p.R1014C)]. Here we show alpha1(I) R-to-C substitutions in three unrelated patients who developed iliac or femoral dissection in early adulthood. In addition, manifestations of classic EDS in Patient 1 [c.1053C>T; R134C (p.R312C); X-position] or osteopenia in Patients 2 [c.1839C>T; R396C (p.R574C); Y-position] and 3 [c.3396C>T; R915C (p.R1093C); Y-position] are seen. Dermal fibroblasts from the patients produced disulfide-bonded alpha1(I)-dimers in approximately 20% of type I collagen, which were efficiently secreted into the medium in case of the R396C and R915C substitution. Theoretical stability calculations of the collagen type I heterotrimer and thermal denaturation curves of monomeric mutant alpha1(I)-collagen chains showed minor destabilization of the collagen helix. However, dimers were shown to be highly unstable. The R134C and R396C caused delayed procollagen processing by N-proteinase. Ultrastructural findings showed collagen fibrils with variable diameter and irregular interfibrillar spaces, suggesting disturbed collagen fibrillogenesis. Our findings demonstrate that R-to-C substitutions in the alpha1(I) chain may result in a phenotype with propensity to arterial rupture in early adulthood. This broadens the phenotypic range of nonglycine substitutions in collagen type I and has important implications for genetic counseling and follow-up of patients carrying this type of mutation.

Authors+Show Affiliations

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17211858

Citation

Malfait, Fransiska, et al. "Three Arginine to Cysteine Substitutions in the Pro-alpha (I)-collagen Chain Cause Ehlers-Danlos Syndrome With a Propensity to Arterial Rupture in Early Adulthood." Human Mutation, vol. 28, no. 4, 2007, pp. 387-95.
Malfait F, Symoens S, De Backer J, et al. Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat. 2007;28(4):387-95.
Malfait, F., Symoens, S., De Backer, J., Hermanns-Lê, T., Sakalihasan, N., Lapière, C. M., Coucke, P., & De Paepe, A. (2007). Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Human Mutation, 28(4), 387-95.
Malfait F, et al. Three Arginine to Cysteine Substitutions in the Pro-alpha (I)-collagen Chain Cause Ehlers-Danlos Syndrome With a Propensity to Arterial Rupture in Early Adulthood. Hum Mutat. 2007;28(4):387-95. PubMed PMID: 17211858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. AU - Malfait,Fransiska, AU - Symoens,Sofie, AU - De Backer,Julie, AU - Hermanns-Lê,Trinh, AU - Sakalihasan,Natzi, AU - Lapière,Charles M, AU - Coucke,Paul, AU - De Paepe,Anne, PY - 2007/1/11/pubmed PY - 2007/5/2/medline PY - 2007/1/11/entrez SP - 387 EP - 95 JF - Human mutation JO - Hum Mutat VL - 28 IS - 4 N2 - Mutations in the COL1A1 and COL1A2 genes, encoding the proalpha1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers-Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly-Xaa-Yaa repeat, few nonglycine substitutions have been reported. Two arginine-to-cysteine substitutions in the alpha1(I)-collagen chain are associated with classic EDS [R134C (p.R312C)] or autosomal dominant Caffey disease with mild EDS features [R836C (p.R1014C)]. Here we show alpha1(I) R-to-C substitutions in three unrelated patients who developed iliac or femoral dissection in early adulthood. In addition, manifestations of classic EDS in Patient 1 [c.1053C>T; R134C (p.R312C); X-position] or osteopenia in Patients 2 [c.1839C>T; R396C (p.R574C); Y-position] and 3 [c.3396C>T; R915C (p.R1093C); Y-position] are seen. Dermal fibroblasts from the patients produced disulfide-bonded alpha1(I)-dimers in approximately 20% of type I collagen, which were efficiently secreted into the medium in case of the R396C and R915C substitution. Theoretical stability calculations of the collagen type I heterotrimer and thermal denaturation curves of monomeric mutant alpha1(I)-collagen chains showed minor destabilization of the collagen helix. However, dimers were shown to be highly unstable. The R134C and R396C caused delayed procollagen processing by N-proteinase. Ultrastructural findings showed collagen fibrils with variable diameter and irregular interfibrillar spaces, suggesting disturbed collagen fibrillogenesis. Our findings demonstrate that R-to-C substitutions in the alpha1(I) chain may result in a phenotype with propensity to arterial rupture in early adulthood. This broadens the phenotypic range of nonglycine substitutions in collagen type I and has important implications for genetic counseling and follow-up of patients carrying this type of mutation. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/17211858/Three_arginine_to_cysteine_substitutions_in_the_pro_alpha__I__collagen_chain_cause_Ehlers_Danlos_syndrome_with_a_propensity_to_arterial_rupture_in_early_adulthood_ L2 - https://doi.org/10.1002/humu.20455 DB - PRIME DP - Unbound Medicine ER -