A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder

Julian C Lui,Jeffrey Baron,Uwe Wintergerst,Adalbert Raimann,Paul Roschger,Nadja Fratzl-Zelman,Bijal Kikani,Gabriele Haeusler,Youn Hee Jee,Lijin Dong,Hironori Hojo

doi:10.1038/s41467-022-28318-4

Julian C Lui, Jeffrey Baron + Show 9 more

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https://doi.org/10.1038/s41467-022-28318-4

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SP7/Osterix is a transcription factor critical for osteoblast maturation and bone formation. Homozygous loss-of-function mutations in SP7 cause osteogenesis imperfecta type XII, but neomorphic (gain-of-new-function) mutations of SP7 have not been reported in humans. Here we describe a de novo dominant neomorphic missense variant (c.926 C > G:p.S309W) in SP7 in a patient with craniosynostosis, cranial hyperostosis, and long bone fragility. Histomorphometry shows increased osteoblasts but decreased bone mineralization. Mice with the corresponding variant also show a complex skeletal phenotype distinct from that of Sp7-null mice. The mutation alters the binding specificity of SP7 from AT-rich motifs to a GC-consensus sequence (typical of other SP family members) and produces an aberrant gene expression profile, including increased expression of Col1a1 and endogenous Sp7, but decreased expression of genes involved in matrix mineralization. Our study identifies a pathogenic mechanism in which a mutation in a transcription factor shifts DNA binding specificity and provides important in vivo evidence that the affinity of SP7 for AT-rich motifs, unique among SP proteins, is critical for normal osteoblast differentiation.

Highlights

SP7/Osterix is a transcription factor critical for osteoblast maturation and bone formation
We demonstrate that this disorder results from a de novo, neomorphic variant in SP7 which redirects the binding specificity of this transcription factor from AT-rich motifs to a GC-consensus sequence, resulting in aberrant gene expression and, abnormal osteoblast differentiation
Bone histomorphometry showed a marked increase in all indices of bone formation and of bone resorption in trabecular bone of the affected patient compared to reference values (Fig. 1g–k, Supplementary Figs. 1, 2)

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SP7/Osterix is a transcription factor critical for osteoblast maturation and bone formation. Our study identifies a pathogenic mechanism in which a mutation in a transcription factor shifts DNA binding specificity and provides important in vivo evidence that the affinity of SP7 for AT-rich motifs, unique among SP proteins, is critical for normal osteoblast differentiation. We studied a patient with a complex skeletal disease involving high bone turnover (increased bone formation and bone resorption) resulting in some regions of increased bone density and other regions of decreased bone density We demonstrate that this disorder results from a de novo, neomorphic variant in SP7 which redirects the binding specificity of this transcription factor from AT-rich motifs to a GC-consensus sequence, resulting in aberrant gene expression and, abnormal osteoblast differentiation. The findings provide the first in vivo evidence that the preference of SP7 for ATrich motifs, unique among SP proteins, is physiologically important for normal osteoblast differentiation

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