Background: Arteriosclerosis and emphysema develop in individuals with
Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused
by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated,
actin-dependent regulator of chromatin, subfamily a-like 1). However,
the mechanism by which the vascular and pulmonary disease arises in SIOD
remains unknown.
Methods: We reviewed the records of 65 patients with SMARCAL1 mutations.
Molecular and immunohistochemical analyses were conducted on autopsy
tissue from 4 SIOD patients.
Results: Thirty-two of 63 patients had signs of arteriosclerosis and 3
of 51 had signs of emphysema. The arteriosclerosis was characterized by
intimal and medial hyperplasia, smooth muscle cell hyperplasia and
fragmented and disorganized elastin fibers, and the pulmonary disease
was characterized by panlobular enlargement of air spaces. Consistent
with a cell autonomous disorder, SMARCAL1 was expressed in arterial and
lung tissue, and both the aorta and lung of SIOD patients had reduced
expression of elastin and alterations in the expression of regulators of
elastin gene expression.
Conclusions: This first comprehensive study of the vascular and
pulmonary complications of SIOD shows that these commonly cause
morbidity and mortality and might arise from impaired elastogenesis.
Additionally, the effect of SMARCAL1 deficiency on elastin expression
provides a model for understanding other features of SIOD
