Separation in genetic pathogenesis of mutations in FBN1-TB5 region between autosomal dominant acromelic dysplasia and Marfan syndrome.

Mutations in the transforming growth factor β-binding protein-like domain 5 (TB5) region of FBN1 can lead to autosomal acromelic dysplasia and Marfan syndrome, which are two diseases with apparently opposite phenotypes. We identified six patients with acromelic dysplasia carrying either the previously reported mutations c.5284G > A (p.Gly1762Ser) and c.5096A > G (p.Tyr1699Cys) or the novel mutation c.5260G > A (p.Gly1754Ser). A systematic review of patients with mutations in the FBN1-TB5 region showed that acromelic dysplasia is caused only by in-frame amino acid substitutions. In contrast, truncating mutations in the FBN1-TB5 have been reported only in Marfan syndrome. Acromelic dysplasia subtypes that share symptoms with Marfan syndrome are associated with FBN1-TB5 disulfide disruptions, which are also commonly found in Marfan syndrome. These results suggest that the type and location of mutations in the FBN1-TB5 region determine the clinical spectrum of fibrillinopathy.