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 patients with progeria, the etiology remains elusive. The L648R single–amino acid substitution blocks prelamin A maturation in mice, modeling a unique patient. Here, we identify prelamin A accumulation as a causative link to craniosynostosis in low bone density, contrasting conventional suture fusion in excessive ossification. The mutation causes skeletal stem cell deficiencies and subsequent osteogenesis. Intrasutural bones present in patients with progeria resemble 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 affect cytoskeleton organization and nucleoskeleton assembly essential for craniofacial skeletogenesis. Our findings provide compelling evidence for nuclear and cytoskeletal defects, causing stem cell–associated osteogenic defects in progeroid disorders.
Authors
Kai Li, Trunee Hsu, Hitoshi Uchida, Tingxi Wu, Susan Michaelis, Howard Worman, Wei Hsu
Figure 4
Suture stem cell deficiency in
