Deletions within COL7A1 Exons Distant from Consensus Splice Sites Alter Splicing and Produce Shortened Polypeptides in Dominant Dystrophic Epidermolysis Bullosa

• Published in: American journal of human genetics 1998-09, Vol.63 (3), p.737-748
• Main Authors: Sakuntabhai, Anavaj, Hammami-Hauasli, Nadja, Bodemer, Christine, Rochat, Ariane, Prost, Catherine, Barrandon, Yann, de Prost, Yves, Lathrop, Mark, Wojnarowska, Fenella, Bruckner-Tuderman, Leena, Hovnanian, Alain
• Format: Article
• Language: English
• Subjects: Abnormal splicing; Adult; Alternative Splicing; Amino Acid Sequence; Anchoring fibrils; Biological and medical sciences; Biopsy; Cells, Cultured; Child; Collagen - genetics; Consensus Sequence; Dermatology; Dominant dystrophic epidermolysis bullosa; Epidermolysis Bullosa Dystrophica - genetics; Epidermolysis Bullosa Dystrophica - metabolism; Epidermolysis Bullosa Dystrophica - pathology; Exon skipping; Exons; Female; Genes, Dominant; Genomic deletion; Genotype; Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue; Heterozygote; Humans; Introns; Keratinocytes - metabolism; Male; Medical sciences; Pedigree; Phenotype; Polymerase Chain Reaction; Procollagen - genetics; Repetitive Sequences, Nucleic Acid; Sequence Deletion; Skin - pathology; Skin - ultrastructure; Type VII collagen
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/302029

We describe two familial cases of dominant dystrophic epidermolysis bullosa (DDEB) that are heterozygous for deletions in COL7A1 that alter splicing, despite intact consensus splice-site sequences. One patient shows a 28-bp genomic deletion (6081del28) in exon 73 associated with the activation of a cryptic donor splice site within this exon; the combination of both defects restores the phase and replaces the last 11 Gly-X-Y repeats of exon 73 by a noncollagenous sequence, Glu-Ser-Leu. The second patient demonstrates a 27-bp deletion in exon 87 (6847del27), causing in-frame skipping of this exon; consensus splice sites, putative branch sites, and introns flanking exons 73 and 87 showed a normal sequence. Keratinocytes from the probands synthesized normal and shortened type VII collagen polypeptides and showed intracellular accumulation of type VII procollagen molecules. This first report of genomic deletions in COL7A1 in DDEB suggests a role for exonic sequences in the control of splicing of COL7A1 pre-mRNA and provides evidence that shortened type VII collagen polypeptides can alter, in a dominant manner, anchoring-fibril formation and can cause DDEB of differing severity.