TY - JOUR
T1 - Compound heterozygosity for a recessive glycine substitution and a splice site mutation in the COL7A1 gene causes an unusually mild form of localized recessive dystrophic epidermolysis bullosa
AU - Terracina, M.
AU - Posterare, P.
AU - Schubert, M.
AU - Sonego, G.
AU - Atzori, F.
AU - Zambruno, G.
AU - Bruckner-Tuderman, L.
AU - Castiglia, D.
PY - 1998
Y1 - 1998
N2 - Type VII collagen is the major component of anchoring fibrils, adhesion structures of stratified epithelia that span the basement membrane region and papillary dermis. Mutations in the gene COL7A1 encoding type VII collagen cause dystrophic epidermolysis bullosa, a clinically heterogeneous autosomal dominant or recessive blistering disorder of the skin and mucous membranes. In this report, we investigate three siblings affected by an unusually mild form of localized recessive dystrophic epidermolysis bullosa who were shown to be compound heterozygotes for novel mutations affecting COL7A1. The maternally inherited mutation is a G→C transversion that converts a codon for glycine to a codon for arginine (G1347R). The paternal mutation is a neutral G→A transition at the last base of exon 70 (5820G→A) that alters the correct splicing of COL7A1 pre-mRNA, giving rise to an aberrant mRNA carrying the in-frame skipping of exon 70 in addition to the full-length RNA transcript carrying the G→yA substitution. Consistent with the normal levels of COL7A1 mRNA transcripts detected by northern analysis, immuneblotting and immunofluorescence studies evidenced that the patient keratinocytes synthesize and secrete normal amounts of stable type VII collagen, which is correctly deposited at the dermal-epidermal junction. In addition, mutated type VII collagen molecules assemble to form numerous, normally shaped anchoring fibrils, as shown by electron microscopic examination. The combination of a recessive glycine substitution with a splice site mutation that permits partially correct splicing therefore leads to a normal expression of mutated type VII collagen molecules with marginally altered biologic activity, and to the extremely mild phenotype observed in our patients.
AB - Type VII collagen is the major component of anchoring fibrils, adhesion structures of stratified epithelia that span the basement membrane region and papillary dermis. Mutations in the gene COL7A1 encoding type VII collagen cause dystrophic epidermolysis bullosa, a clinically heterogeneous autosomal dominant or recessive blistering disorder of the skin and mucous membranes. In this report, we investigate three siblings affected by an unusually mild form of localized recessive dystrophic epidermolysis bullosa who were shown to be compound heterozygotes for novel mutations affecting COL7A1. The maternally inherited mutation is a G→C transversion that converts a codon for glycine to a codon for arginine (G1347R). The paternal mutation is a neutral G→A transition at the last base of exon 70 (5820G→A) that alters the correct splicing of COL7A1 pre-mRNA, giving rise to an aberrant mRNA carrying the in-frame skipping of exon 70 in addition to the full-length RNA transcript carrying the G→yA substitution. Consistent with the normal levels of COL7A1 mRNA transcripts detected by northern analysis, immuneblotting and immunofluorescence studies evidenced that the patient keratinocytes synthesize and secrete normal amounts of stable type VII collagen, which is correctly deposited at the dermal-epidermal junction. In addition, mutated type VII collagen molecules assemble to form numerous, normally shaped anchoring fibrils, as shown by electron microscopic examination. The combination of a recessive glycine substitution with a splice site mutation that permits partially correct splicing therefore leads to a normal expression of mutated type VII collagen molecules with marginally altered biologic activity, and to the extremely mild phenotype observed in our patients.
KW - Anchoring fibrils
KW - Inherited blistering skin diseases
KW - Molecular genetics
KW - Type VII collagen
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U2 - 10.1046/j.1523-1747.1998.00397.x
DO - 10.1046/j.1523-1747.1998.00397.x
M3 - Article
C2 - 9804332
AN - SCOPUS:0031767968
VL - 111
SP - 744
EP - 750
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 5
ER -