Abstract
Mutations in LMNA, encoding nuclear lamina protein Lamin A/C, cause premature aging disorders, most notably Hutchinson-Gilford Progeria Syndrome. Despite obvious skull abnormalities in progeroid patients, the disease-causing mechanism remains elusive. The L648R single amino acid substitution blocks prelamin A maturation in mice, modeling a unique human patient. Here, we describe skull deformities in premature aging caused by aberrant suture fusion resembling those of patients with craniosynostosis. Further examinations identify prelamin A accumulation causatively linked to multiple suture synostoses in low bone density. This etiology is distinct from conventional suture fusion mediated by excessive ossification. In addition, the mutation disrupts skeletal stem cell stemness and subsequent stem cell-mediated proliferation and differentiation in osteogenesis. Intrasutural bones present in progeroid patients are highly reminiscent of synostosis caused by stem cell exhaustion. Comparative gene expression profiling further reveals cytoskeletal dynamics associated with skeletogenic cell aging and suture patency in mice and humans. Functional studies demonstrate that abnormal structures of progeric nuclei caused by prelamin A accumulation affect cytoskeleton organization and nucleoskeleton assembly essential for craniofacial skeletogenesis. Pharmacogenetic analyses indicate alleviation of osteogenic defects via actin polymerization. Our findings provide compelling evidence for nuclear and cytoskeletal defects, mediating stem cell-associated osteogenic deformities in progeroid disorders.
Authors
Kai Li, Trunee Hsu, Hitoshi Uchida, Tingxi Wu, Susan Michaelis, Howard J. Worman, Wei Hsu
