Cutis Laxa Arising from Frameshift Mutations in Exon 30 of the Elastin Gene (ELN)*

Congenital cutis laxa, a rare syndrome with marked skin laxity and pulmonary and cardiovascular compromise, is due to defective elastic fiber formation. In several cases, skin fibroblast tropoelastin production is markedly reduced yet reversed in vitro by transforming growth factor-β treatment. We previously showed that this reversal was due to elastin mRNA stabilization in one cell strain, and here this behavior was confirmed in skin fibroblasts from two generations of a second family. cDNA sequencing and heteroduplex analysis of elastin gene transcripts from three fibroblast strains in two kindreds now identify two frameshift mutations (2012ΔG and 2039ΔC) in elastin gene exon 30, thus leading to missense C termini. No other mutations were present in theELN cDNA sequences of all three affected individuals. Transcripts from both alleles in each kindred were unstable and responsive to transforming growth factor-β. Exons 22, 23, 26A, and 32 were always absent. Since exon 30 underwent alternative splicing in fibroblasts, we speculate that a differential splicing pattern could conceivably lead to phenotypic rescue. These two dominant-acting, apparently de novo mutations in the elastin gene appear to be responsible for qualitative and quantitative defects in elastin, resulting in the cutis laxa phenotype.

[1]  H. Starklint,et al.  Cutis laxa: autosomal dominant inheritance in five generations , 1991, Clinical genetics.

[2]  J. Uitto,et al.  Demonstration of elastin gene expression in human skin fibroblast cultures and reduced tropoelastin production by cells from a patient with atrophoderma. , 1985, The Journal of clinical investigation.

[3]  C. Morris,et al.  Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients. , 1995, American journal of human genetics.

[4]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[5]  J. Rosenbloom,et al.  Insulin-like growth factor-I regulates transcription of the elastin gene. , 1993, The Journal of biological chemistry.

[6]  Seymour,et al.  Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect. , 1993, The Journal of clinical investigation.

[7]  W. Reardon,et al.  Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis. , 1997, Human molecular genetics.

[8]  R. Pyeritz,et al.  Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome. , 1990, The New England journal of medicine.

[9]  M. Mattei,et al.  Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes , 1991, Nature.

[10]  L. Maquat,et al.  Mammalian nonsense codons can be cis effectors of nuclear mRNA half-life , 1994, Molecular and cellular biology.

[11]  Z. Werb,et al.  Blockage of tropoelastin secretion by monensin represses tropoelastin synthesis at a pretranslational level in rat smooth muscle cells , 1985, Molecular and cellular biology.

[12]  L. Peltonen,et al.  Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome , 1994, Nature Genetics.

[13]  J. Uitto,et al.  Molecular mechanisms of cutaneous aging. Age-associated connective tissue alterations in the dermis. , 1989, Journal of the American Academy of Dermatology.

[14]  J. Rosenbloom,et al.  Cloning of full-length elastin cDNAs from a human skin fibroblast recombinant cDNA library: further elucidation of alternative splicing utilizing exon-specific oligonucleotides. , 1988, The Journal of investigative dermatology.

[15]  Ada Hamosh,et al.  Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene , 1991, Nature.

[16]  P. Byers,et al.  Heterogeneity of elastin expression in cutis laxa fibroblast strains. , 1989, The Journal of investigative dermatology.

[17]  M. D. de Santi,et al.  The pallid mouse. A model of genetic alpha 1-antitrypsin deficiency. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[18]  R. Pierce,et al.  Heterogeneity of rat tropoelastin mRNA revealed by cDNA cloning. , 1990, Biochemistry.

[19]  J. Rosenbloom,et al.  Extracellular matrix 4: The elastic fiber , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  C. Morris,et al.  Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. , 1997, Human molecular genetics.

[21]  C A Morris,et al.  Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene. , 1994, The Journal of clinical investigation.

[22]  Colleen A. Morris,et al.  The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis , 1993, Cell.

[23]  J. Davidson,et al.  Transforming growth factor-beta reverses a posttranscriptional defect in elastin synthesis in a cutis laxa skin fibroblast strain. , 1995, The Journal of clinical investigation.

[24]  J. Rosenbloom,et al.  Cutis laxa: reduced elastin gene expression in skin fibroblast cultures as determined by hybridizations with a homologous cDNA and an exon 1-specific oligonucleotide. , 1988, The Journal of biological chemistry.

[25]  J. Rosenbloom,et al.  Structure of the Elastin Gene and Alternative Splicing of Elastin mRNA , 1990 .

[26]  J. Pachter,et al.  Autoregulation of tubulin expression is achieved through specific degradation of polysomal tubulin mRNAs , 1987, Cell.

[27]  J. Rosenbloom,et al.  A to G polymorphism in ELN gene. , 1991, Nucleic acids research.

[28]  J. Rosenbloom,et al.  Structure of the 3' region of the human elastin gene: great abundance of Alu repetitive sequences and few coding sequences. , 1987, Connective tissue research.

[29]  R. Mecham,et al.  The cysteine residues in the carboxy terminal domain of tropoelastin form an intrachain disulfide bond that stabilizes a loop structure and positively charged pocket. , 1992, Biochemical and biophysical research communications.

[30]  M. Keating.  Genetic approaches to cardiovascular disease. Supravalvular aortic stenosis, Williams syndrome, and long-QT syndrome. , 1995, Circulation.

[31]  R. Young,et al.  Ultrastructural analysis of skin and aorta from a patient with Menkes disease. , 1994, Experimental and molecular pathology.

[32]  Y. Kitano,et al.  Cutis laxa with ultrastructural abnormalities of elastic fiber. , 1989, Journal of the American Academy of Dermatology.

[33]  Patricia Spallone,et al.  Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome , 1993, Nature Genetics.

[34]  M. Tassabehji,et al.  An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa. , 1998, Human molecular genetics.

[35]  Lynn Y. Sakal.  Connective tissue and its heritable disorders: Molecular, genetic and medical aspects , 1993 .

[36]  S. Crawford,et al.  Characterization of a type VI collagen-related Mr-140 000 protein from cutis-laxa fibroblasts in culture. , 1985, The Biochemical journal.

[37]  D. Volpin,et al.  Identification of a TGF-β Responsive Element in the Human Elastin Promoter , 1994 .