RESUMO
The cyclic adenosine monophosphate responsive element binding protein 3-like 1 (CREB3L1) gene codes for the endoplasmic reticulum stress transducer old astrocyte specifically induced substance (OASIS), which has an important role in osteoblast differentiation during bone development. Deficiency of OASIS is linked to a severe form of autosomal recessive osteogenesis imperfecta (OI), but only few patients have been reported. We identified the first homozygous pathogenic missense variant [p.(Ala304Val)] in a patient with lethal OI, which is located within the highly conserved basic leucine zipper domain, four amino acids upstream of the DNA binding domain. In vitro structural modeling and luciferase assays demonstrate that this missense variant affects a critical residue in this functional domain, thereby decreasing the type I collagen transcriptional binding ability. In addition, overexpression of the mutant OASIS protein leads to decreased transcription of the SEC23A and SEC24D genes, which code for components of the coat protein complex type II (COPII), and aberrant OASIS signaling also results in decreased protein levels of SEC24D. Our findings therefore provide additional proof of the potential involvement of the COPII secretory complex in the context of bone-associated disease.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Estresse do Retículo Endoplasmático/genética , Proteínas do Tecido Nervoso/genética , Osteogênese Imperfeita/genética , Domínios Proteicos/genética , Astrócitos/metabolismo , Astrócitos/patologia , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/genética , Pré-Escolar , Colágeno Tipo I/química , Colágeno Tipo I/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/química , Proteínas de Ligação a DNA/genética , Feminino , Homozigoto , Humanos , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Proteínas do Tecido Nervoso/química , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia , Linhagem , Fenótipo , Ligação Proteica , Proteínas de Transporte Vesicular/genéticaRESUMO
Type I collagen is the predominant protein of connective tissues such as skin and bone. Mutations in the type I collagen genes (COL1A1 and COL1A2) mainly cause osteogenesis imperfecta (OI). We describe a patient with clinical signs of Ehlers-Danlos syndrome (EDS), including fragile skin, easy bruising, recurrent luxations, and fractures resembling mild OI. Biochemical collagen analysis of the patients' dermal fibroblasts showed faint overmodification of the type I collagen bands, a finding specific for structural defects in type I collagen. Bidirectional Sanger sequencing detected an in-frame deletion in exon 44 of COL1A1 (c.3150_3158del), resulting in the deletion of three amino acids (p.Ala1053_Gly1055del) in the collagen triple helix. This COL1A1 mutation was hitherto identified in four probands with lethal OI, and never in EDS patients. As the peaks on the electropherogram corresponding to the mutant allele were decreased in intensity, we performed next generation sequencing of COL1A1 to study mosaicism in skin and blood. While approximately 9% of the reads originating from fibroblast gDNA harbored the COL1A1 deletion, the deletion was not detected in gDNA from blood. Most likely, the mild clinical symptoms observed in our patient can be explained by the mosaic state of the mutation.