Comparative analysis of the two extremes of -mutated autosomal dominant disease spectrum: from clinical phenotypes to cellular and molecular findings.

Non-randomly distributed missense mutations of () can lead to a spectrum of autosomal dominant-inherited skeletal malformations caused by bone hypoplasia, including Larsen syndrome (LS), atelosteogenesi-I (AO-I), atelosteogenesi-I (AO-III) and boomerang dysplasia (BD). Among this spectrum of diseases, LS causes a milder hypoplasia of the skeletal system, compared to BD's much more severe symptoms. Previous studies revealed limited molecular mechanisms of related diseases but most of them were carried out with HEK293 cells from the kidney which could not reproduce s specificity to skeletal tissues. Instead, we elected to use ATDC5, a chondrogenic stem cell line widely used to study endochondral osteogenesis. In this study, we established -transfected ATDC5 cell model. We reported a pedigree of LS with mutation of and reviewed a case of BD with mutation of . Using the ATDC5 cell model above, we compared cellular and molecular phenotypes of BD-associated and LS-associated . We found that while both phenotypes had an increased expression of Runx2, FLNB-expressing ATDC5 cells presented globular aggregation of FLNB protein and increased cellular apoptosis rate while FLNB-expressing ATDC5 cells presented evenly distributed FLNB protein and decreased cellular migration. These findings support our explanation for the cause of differences in clinical phenotypes between LS and BD. Our study makes a comparative analysis of two extremes of the -mutated autosomal dominant spectrum, relating known clinical phenotypes to our new cellular and molecular findings. These results indicated next steps for future research on the role of in the physiological process of endochondral osteogenesis.