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Unexpected genotype‐phenotype associations in bone dysplasias driven by whole exome sequencing (213.2)
Author(s) -
Lee Brendan
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.213.2
Subject(s) - osteogenesis imperfecta , phenotype , mendelian inheritance , exome sequencing , biology , genetics , extracellular matrix , exome , osteoporosis , bioinformatics , gene , endocrinology , anatomy
Over the past three decade the study of Mendelian forms of skeletal dysplasias best represented by Osteogenesis Imperfecta (OI) has led to the identification of disease mechanisms that affect both the quality and quantity of bone. This has been revolutionized by next generation sequencing and whole exome analysis. They have led to the discovery of enormous genetic heterogeneity that is becoming the rule for genetic phenotypes. In the case of OI, structural mutations in the most abundant components of matrix type I collagen, protein complexes that modify and chaperone collagen, and most recently components of signaling pathways have all been implicated. Together they underscore the factors the regulate mineralization of extracellular matrix and the differentiation and function of osteoblasts, osteoclasts, and osteocytes. In so doing they have also pointed to novel therapeutic strategies that may also need to be customized based on nature and consequence of mutation. Finally, the most recent data on the mutations that affect matrix‐cell signaling and cell‐cell signaling point to overlap with early onset osteoporosis phenotypes.