Mutations in fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS) characterized by short stature, eye defects, hypermuscularity and thickened skin.
Mutations in several genes have been identified for these disorders (including latent transforming growth factor β (TGF-β)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network.
Moreover, mutations in specific regions of FBN1 can result in the opposite features of short stature and brachydactyly characteristic of Weill-Marchesani syndrome and other acromelic dysplasias.
FBN1 variants are responsible for the related connective tissue disorders, grouped under the generic term of type-1 fibrillinopathies, which include Marfan syndrome (MFS), MASS syndrome (Mitral valve prolapse, Aortic enlargement, Skin and Skeletal findings, Acromicric dysplasia, Familial ectopia lentis, Geleophysic dysplasia 2, Stiff skin syndrome, and dominant Weill-Marchesani syndrome.
Today we know that mutations in fibrillin-1 cause the Marfan syndrome as well as Weill-Marchesani syndrome (and other acromelic dysplasias) and result in opposite clinical phenotypes: tall or short stature; arachnodactyly or brachydactyly; joint hypermobility or stiff joints; hypomuscularity or hypermuscularity.
Mutations in FBN1, ADAMTS10, or ADAMTS17 cause Weill-Marchesani syndrome by disrupting the microfibrillar environment, while geleophysic dysplasia is associated with enhanced TGF-β signaling mediated through mutations in FBN1 or ADAMTSL2.
Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice.
Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice.
The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome.