Insufficiency or defectiveness of type I collagen is the cause of osteogenesis imperfect (OI), an inherited disorder characterized by abnormal bone development with an increased lifetime risk of fractures. Exome sequencing of a family presenting with OI phenotypes ranging from mild with few fractures to prenatal lethality revealed a mutation in CREB3L1, encoding a basic leucine zipper (bZIP) transcription factor. CREB3L1 has been reported once before in association with OI but the disease mechanism is still unclear. Collagen proteins are quite large and their transport from the endoplasmic reticulum (ER) to the Golgi for packaging and eventual secretion is achieved using specialized secretory machinery. A closely related protein to CREB3L1, CREB3L2, has a role in regulating one such pathway in chondrocytes and is important for proper cartilage formation. Impaired functionality of CREB3L1 due to mutation may perturb the same or a related pathway in osteoblasts and lead to reduced type I collagen in bone, explaining the OI. There is also evidence that CREB3L1 operates in cell-type specific physiological ER stress pathways that may contribute to the phenotype. Fibroblasts from the proband are available but do not express CREB3L1. CREB3L1-associated OI will be modeled using both induced pluripotent stem cell (iPSC)-derived osteoblasts from patient cells bearing the deletion and zebrafish engineered with the family mutation. These models will be used to look for evidence of the impaired secretion that is hypothesized and to define the role of CREB3L1 in various pathways that operate during bone development. Both models will serve as confirmation of CREB3L1 as an OI disease gene and potentially as tools for the design of new drugs or treatments for brittle bone disease.

Public Health Relevance

Elucidating the role of CREB3L1 in osteogenesis imperfecta (OI) will aid in the future diagnosis and counseling of OI families and lay the foundation upon which genetic therapies may eventually be based, while the models themselves may be useful for testing new drugs or treatments in the interim. A deeper understanding of a number of pathways and mechanisms including bone development, cellular secretion, and cell-type specific endoplasmic reticulum stress responses may be gained, with the potential to impact medicine beyond a single genetic disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Chen, Faye H
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University of Washington
Schools of Medicine
United States
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Keller, Rachel B; Tran, Thao T; Pyott, Shawna M et al. (2018) Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. Genet Med 20:411-419