A novel mutation in COL1A2 leads to osteogenesis imperfecta/Ehlers-Danlos overlap syndrome with brachydactyly

Abstract

Osteogenesis imperfecta (OI) is mainly characterized by bone fragility and Ehlers-Danlos syndrome (EDS) by connective tissue defects. Mutations in COL1A1 or COL1A2 can lead to both syndromes. OI/EDS overlap syndrome is mostly caused by helical mutations near the amino-proteinase cleavage site of type I procollagen. In this study, we identified a Thai patient having OI type III, EDS, brachydactyly, and dentinogenesis imperfecta. His dentition showed delayed eruption, early exfoliation, and severe malocclusion. For the first time, ultrastructural analysis of the tooth affected with OI/EDS showed that the tooth had enamel inversion, bone-like dentin, loss of dentinal tubules, and reduction in hardness and elasticity, suggesting severe developmental disturbance. These severe dental defects have never been reported in OI or EDS. Exome sequencing identified a novel de novo heterozygous glycine substitution, c.3296G > A, p.Gly1099Glu, in exon 49 of COL1A2 . Three patients with mutations in the exon 49 of COL1A2 were previously reported to have OI with brachydactyly and intracranial hemorrhage. Notably, two of these three patients did not show hyperextensible joints and hypermobile skin, while our patient at the age of 5 years had not developed intracranial hemorrhage. Here, we demonstrate that the novel glycine substitution in the carboxyl region of alpha2(I) collagen triple helix leads to OI/EDS with brachydactyly and severe tooth defects, expanding the genotypic and phenotypic spectra of OI/EDS overlap syndrome.

Tooth ultrastructure of a novel COL1A2 mutation expanding its genotypic and phenotypic spectra

“…In addition, many lines of evidence indicate the pathogenic and causative roles of the c.758G > T (p.Gly253Val) for OI. First, glycine substitutions were demonstrated to be causative of OI in a large number of cases worldwide (Budsamongkol et al, 2019;Hemwong et al, 2020;Marini et al, 2017;Udomchaiprasertkul et al, 2020). Second, the substitutions of glycine, the smallest amino acid, were shown to alter…”

Comparative transcriptome profiles of human dental pulp stem cells from maxillary and mandibular teeth

“…COL1A1 and COL1A2 encode for type 1 collagen, which is the most common collagen type in humans 32 . Variations in COL1A1 and COL1A2 are associated with osteogenesis imperfecta and dentinogenesis imperfecta causing brittle dentin 33 – 36 . Col1a1 mutant mice have a mandibular side shift and short craniofacial, maxillary, and mandibular morphometric indices, as well as a class III dental occlusion.…”

MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders

“…Typically, OI is most often found to be caused by autosomal dominant mutations in either of the genes that encode for collagen type 1 alpha chains, COL1A1 or COL1A2 , causing an alteration in the structure or function of collagen type 1, the most abundant protein of bone extracellular matrix [ 108 , 110 – 112 ]. Mutations in genes involved in posttranslational modification of collagen ( CRTAP, PPIB, LEPRE1/P3H 1) [ 113 – 115 ], folding ( SERPINH1, FKBP10 ) [ 13 , 116 ], intracellular trafficking ( SEC24D ) [ 117 ], and extracellular processing ( BMP1 ) [ 118 , 119 ] have also been described to cause OI as a result of autosomal recessive inheritance.…”