Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease

Mutations in distant regulatory elements can have a negative impact on human development and health, yet because of the difficulty of detecting these critical sequences, we predominantly focus on coding sequences for diagnostic purposes. We have undertaken a comparative sequence-based approach to ch...

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Bibliographic Details
Published in:Genome research 2005-07, Vol.15 (7), p.928-935
Main Authors: Loots, Gabriela G, Kneissel, Michaela, Keller, Hansjoerg, Baptist, Myma, Chang, Jessie, Collette, Nicole M, Ovcharenko, Dmitriy, Plajzer-Frick, Ingrid, Rubin, Edward M
Format: Article
Language:English
Subjects:
Animals
Bone Density - genetics
Bone Morphogenetic Proteins - genetics
Enhancer Elements, Genetic
Gene Deletion
Gene Expression Regulation, Developmental
Genetic Linkage
Genetic Markers - genetics
Humans
Hyperostosis - genetics
Letters
Male
Mice
Mice, Transgenic
Phenotype
Rats
Sequence Alignment
Tumor Cells, Cultured
Untranslated Regions
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Summary:Mutations in distant regulatory elements can have a negative impact on human development and health, yet because of the difficulty of detecting these critical sequences, we predominantly focus on coding sequences for diagnostic purposes. We have undertaken a comparative sequence-based approach to characterize a large noncoding region deleted in patients affected by Van Buchem (VB) disease, a severe sclerosing bone dysplasia. Using BAC recombination and transgenesis, we characterized the expression of human sclerostin (SOST) from normal (SOST(wt)) or Van Buchem (SOST(vbDelta) alleles. Only the SOST(wt) allele faithfully expressed high levels of human SOST in the adult bone and had an impact on bone metabolism, consistent with the model that the VB noncoding deletion removes a SOST-specific regulatory element. By exploiting cross-species sequence comparisons with in vitro and in vivo enhancer assays, we were able to identify a candidate enhancer element that drives human SOST expression in osteoblast-like cell lines in vitro and in the skeletal anlage of the embryonic day 14.5 (E14.5) mouse embryo, and discovered a novel function for sclerostin during limb development. Our approach represents a framework for characterizing distant regulatory elements associated with abnormal human phenotypes.
ISSN:1088-9051
1549-5469
DOI:10.1101/gr.3437105