Genotype-phenotype correlation in recessive dystrophic epidermolysis bullosa: when missense doesn't make sense.
Genotype-phenotype correlation in recessive dystrophic epidermolysis bullosa: when missense doesn't make sense.
复制标题
隐性营养不良性大疱性表皮松解症的基因型-表型相关性：当错义没有意义时。
DOI：
10.1111/j.0022-202x.2005.23650.x
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
J. McGrath
中科院分区：
文献类型：
--
作者：
V. Wessagowit;Soo;Se Woong Oh;J. McGrath
All forms of dystrophic epidermolysis bullosa (DEB) result from mutations in the gene encoding type VII collagen, COL7A1, the major component of anchoring fibrils at the dermal–epidermal junction (Christiano et al, 1994). Approximately 200 different pathogenic mutations have been reported and, to some extent, a paradigm for genotype– phenotype correlation has emerged. Typically, severe generalized forms of recessive DEB result from premature termination codons on both COL7A1 alleles (Uitto and Christiano, 1994), whereas autosomal dominant cases are caused by heterozygous glycine substitutions within the collagenous triple helix (Christiano et al, 1994). It is clear, however, that the clinical diversity seen in both recessive and dominant forms of DEB is mirrored by a spectrum of mutations in COL7A1, with clinical heterogeneity partially being explained through an accumulating database of other missense, splice site, or insertion/deletion frameshift mutations (Whittock et al, 1999). In recessive DEB, the repertoire of mutations includes: nonsense mutations, splice site mutations, internal deletions or insertions, ‘‘silent’’ glycine substitutions within the triple helix, and non-glycine missense mutations within the triple helix or non-collagenous NC-2 domain (Whittock et al, 1999). We now report an example of a pathogenic missense mutation within the NC-1 domain. The nucleotide substitution results in cryptic splicing and an in-frame deletion of 29 amino acids from the part of the protein with cartilage matrix protein homology, thus providing clinicopathological evidence for a new type of mutation in recessive DEB and demonstrating the importance of this part of type VII collagen in epidermal–dermal adhesion. The proband is an 8-y-old Korean male with a history of blisters and erosions at birth but only limited trauma-induced blistering during infancy. But at the age of 7 y, there was a worsening of blisters with development of milia and scarring. There was never any history of skin itching. Physical examination revealed bullae (some of which were hemorrhagic), erosions, scars, and milia on his lower legs, hands, feet, and pinnae. He also had dystrophic nails with some loss of toenails (Fig 1A). Notably, the skin on his shins was the most affected site (Fig 1B). No other family member was affected and both parents are clinically normal. The clinical features were suggestive of a mild form of recessive DEB or possibly de novo dominant disease, including the pretibial variant. Indirect immunofluorescence microscopy of the affected individual’s skin using an anti-type VII collagen monoclonal antibody (LH7.2; Fig 1C) (Heagerty et al, 1986) showed bright labeling at the dermal–epidermal junction that was of an intensity very similar to normal control skin (Fig 1D). This finding is unhelpful in establishing the precise diagnosis and in distinguishing between mild recessive and de novo dominant DEB. Following ethical approval, informed consent, and in compliance with the Helsinki guidelines, DNA extraction from peripheral blood samples from the patient and his parents was performed using QIAamp DNA Blood Midi Kits (Qiagen, Crawley, West Sussex, UK). PCR amplification of the COL7A1 gene was performed, and heteroduplex analysis was carried out as described previously (Christiano et al, 1997b). Any fragment with a different mobility to amplified control DNA was sequenced using dRhodamine dye terminator technology on an ABI 310 capillary system (PE Biosystems, Warrington, UK). Sequencing of genomic DNA showed that the patient is heterozygous for two nucleotide substitutions: 341G4T in exon 3 and 5797C4T in exon 70, the former inherited from the mother and the latter from the father (GenBank No. L02870). The mutation 341G4T converts a glycine (GGG) residue to valine (GTG) residue, and is designated G114V (Fig 2A). The 5797C4T mutation changes arginine (CGA) to a premature stop codon (TGA) and is designated R1933X (Fig 2B). Thus, the affected individual is a compound heterozygote for the mutations G114V/R1933X in COL7A1. The mutation R1933X has been reported once previously in an individual with Hallopeau–Siemens recessive DEB (compound heterozygote for R578X/R1933X) (Whittock et al, 1999) but G114V is a new finding. The possibility of this missense change being a non-pathogenic polymorphism was excluded by direct sequencing of 100 ethnically matched (Korean/Chinese/Japanese) control chromosomes. To assess the potential pathogenicity of the mutation G114V, the genomic sequence was examined using the Delila software package (Schneider, 1997a), which scans genomic sequences with weight matrices for sites with positive Ri (individual information content) values, and the results were displayed using the Sequence Walker program (Schneider, 1997b). The 341G4T nucleotide substitution, located 86 nucleotides upstream from the exon 3 natural donor, shows high semblance to the donor splice site consensus (Zhang, 1998) and activates a new strong cryptic site (Ri value increases from 0.0 to 8.2 bits) at this position (Fig 2C and D), whereas the natural donor site remains Abbreviation: DEB, dystrophic epidermolysis bullosa
由于 COL7A1 基因内部缺失的外显子跳过而导致开放阅读框的恢复。
DOI：
--
发表时间：
1998
期刊：
Laboratory investigation; a journal of technical methods and pathology.
影响因子：
--
作者：
Cserhalmi-Friedman,PB;McGrath,JA;Mellerio,JE;Romero,R;Salas-Alanis,JC;Paller,AS;Dietz,HC;Christiano,AM
通讯作者：
Christiano,AM
VII 型胶原蛋白的大非胶原结构域 (NC-1) 是氨基末端且嵌合的。
影响因子：
3.5
作者：
Christiano,AM;Rosenbaum,LM;Chung-Honet,LC;Parente,MG;Woodley,DT;Pan,TC;Zhang,RZ;Chu,ML;Burgeson,RE;Uitto,J
通讯作者：
Uitto,J