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.
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.
Malfait
Fransiska
F
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Symoens
Sofie
S
De Backer
Julie
J
Hermanns-Lê
Trinh
T
Sakalihasan
Natzi
N
Lapière
Charles M
CM
Coucke
Paul
P
De Paepe
Anne
A
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001851:Bone Diseases, Metabolic / Q000150:complications / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000235:genetics; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004535:Ehlers-Danlos Syndrome / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005263:Femoral Artery; D006801:Humans; D007083:Iliac Artery; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000235:genetics; D012422:Rupture, Spontaneous / Q000235:genetics*
C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D012333:RNA, Messenger; D003094:Collagen; D001120:Arginine; D003545:Cysteine