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

Julian C. Lui (), Adalbert Raimann, Hironori Hojo, Lijin Dong, Paul Roschger, Bijal Kikani, Uwe Wintergerst, Nadja Fratzl-Zelman, Youn Hee Jee, Gabriele Haeusler and Jeffrey Baron
Additional contact information
Julian C. Lui: National Institutes of Health
Adalbert Raimann: Medical University of Vienna
Hironori Hojo: Center for Disease and Integrative Medicine, University of Tokyo
Lijin Dong: Genetic Engineering Core, National Eye Institute, National Institute of Health
Paul Roschger: Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital
Bijal Kikani: National Institutes of Health
Uwe Wintergerst: Hospital of Braunau
Nadja Fratzl-Zelman: Vienna Bone and Growth Center
Youn Hee Jee: National Institutes of Health
Gabriele Haeusler: Medical University of Vienna
Jeffrey Baron: National Institutes of Health

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28318-4

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