Novel ELN Mutations and Vascular Phenotype in Autosomal Dominant Cutis Laxa. E. Lawrence1, M. McGowan1, K. Levine1, C. Lorenchick1, S. Alkan1, H. Salvaggio2, A. Zaenglein2, M. Bodzioch3, A. Kiss4, M. Siefring5, Z. Urban1 1) Department of Human Genetics University of Pittsburgh; 2) Department of Dermatology Penn State Milton S. Hersey Medical Center; 3) Jagiellonian University Medical College; 4) Dept. of Clinical Genetics Universidade Federale de Ciencias de Porto Allegre; 5) Stamford Skin and Medical Centre.

   Cutis laxa (CL) is an inherited skin disease with remarkable locus heterogeneity. Mutations in the elastin gene (ELN) cause autosomal dominant cutis laxa (ADCL). We have sequenced ELN for exons 30-34 in 89 consecutive probands with CL and a subset of 20 of these probands for all 34 exons in the gene. Mutations were identified in 11 probands. Three families had a c.2296delA in exon 32, one presented with a c.2177delC in exon 30 and one with a c.2137delG in exon 30, all of which were previously published for other families. Several families had previously unreported mutations, a c.2184delT in exon 30 and a c.2351delG in exon 34. The more interesting of the unreported mutations were splice site changes that were found in the remaining four families. Three unrelated probands had the same de novo change a c.2132-7C>A located between exons 33 and 34 which activated a cryptic splice site at position -5 and caused an addition of five nucleotides between exons 33 and 34. This insertion led to a frame-shift which extended the open reading frame. The remaining proband not only had a splice change but it was located outside the canonical region of exon 30-34 where most of the previously published mutations had been located. This family has a c.133+1delG in intron 2 which also activated a cryptic splice site and led to a 28-amino acid in frame insertion between exons 2 and 3. An examination of the origin of the mutations was possible in 10 families, 2 showing inherited, and the remaining 8 de novo mutations. In addition to CL, 4/11 affected individuals had mild-moderate obstructive pulmonary disease and one had a mild aortic root dilatation. There were also 5 cases of arterial tortuosity and two of venous tortuosity both of whom had the mutation c.2132-7C>A. Immunoblotting showed elevated canonical, but unaffected non-canonical transforming growth factor-beta signaling despite unaltered extracellular TGF activity in fibroblasts from patients with ELN mutations. We conclude that ELN-related CL explains approximately 12% of cutis laxa cases and elevated TGF signaling is a disease mechanism in ADCL shared with other connective tissue diseases.

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