# Stem cell–associated osteogenic deficiency causes craniofacial deformities with progeroid accumulation of prelamin A

## TL;DR

A mutation in the LMNA gene causes premature aging and skull deformities by affecting stem cells and bone formation.

## Contribution

The study identifies prelamin A accumulation as a novel cause of craniosynostosis in progeroid disorders.

## Key findings

- Prelamin A accumulation causes craniosynostosis in low bone density, distinct from conventional suture fusion.
- Lmna mutation leads to skeletal stem cell deficiencies and impaired osteogenesis.
- Progeric nuclei disrupt cytoskeleton and nucleoskeleton, essential for craniofacial development.

## 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.

Craniosynostosis in mice with progeroid Lmna mutation