Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta.
Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta.
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DOI：
10.3892/ijmm.18.2.333
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发表时间：
2006-08
影响因子：
5.4
通讯作者：
Hiroyuki Nakamura;D. Sawamura;Maki Goto;Hideki Nakamura;M. Kida;T. Ariga;Y. Sakiyama;K. Tomizawa-
中科院分区：
文献类型：
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作者：
Hiroyuki Nakamura;D. Sawamura;Maki Goto;Hideki Nakamura;M. Kida;T. Ariga;Y. Sakiyama;K. Tomizawa-
非herlitz结缔性大疱性表皮松解症（nH-JEB）表现为皮肤起泡、萎缩和牙釉质发育不全。大多数nH-JEB患者在编码XVII型胶原蛋白的基因COL17A1中存在突变。具有单一COL17A1突变的杂合子，nH-JEB缺陷携带者，可能只表现为牙釉质发育不全。在这项研究中，为了进一步阐明COL17A1突变表型/基因型相关性，我们研究了两个不相关的nH-JEB家族。此外，我们假设COL17A1突变可能导致或加重了釉质发育不全（AI）患者的牙釉质发育不全，这种患者的特征是牙釉质形成缺陷，没有其他系统性表现。因此，我们对来自两个AI家族的三名患者进行了COL17A1突变分析。一名nH-JEB患者没有COL17A1表达，是新型过早终止密码子（PTC）突变1285delA和Q1387X的复合杂合子。此外，在第二例nH-JEB患者中发现COL17A1表达减少，该患者与新型PTC突变4335delC纯合，这是迄今为止鉴定的最羧基端的PTC突变。由于无义介导的mRNA衰变，这些PTC突变的位置被认为不会影响COL17A1转录本丢失的效果，因此不会影响nH-JEB表型的严重程度。该研究首次表明，XVII型胶原羧基PTC突变可导致nH-JEB中多肽的截断表达恢复和较轻的临床疾病严重程度。相反，我们未能在AI患者中检测到任何致病性COL17A1缺陷，无论是在AI患者的外显子中还是在内含子-外显子边界内。本研究进一步了解了COL17A1突变引起nH-JEB，并明确了nH-JEB和AI疾病釉质发育不全的不同机制。
Non-Herlitz junctional epidermolysis bullosa (nH-JEB) disease manifests with skin blistering, atrophy and tooth enamel hypoplasia. The majority of patients with nH-JEB harbor mutations in COL17A1, the gene encoding type XVII collagen. Heterozygotes with a single COL17A1 mutation, nH-JEB defect carriers, may exhibit only enamel hypoplasia. In this study, to further elucidate COL17A1 mutation phenotype/ genotype correlations, we examined two unrelated families with nH-JEB. Furthermore, we hypothesized that COL17A1 mutations might underlie or worsen the enamel hypoplasia seen in amelogenesis imperfecta (AI) patients that are characterized by defects in tooth enamel formation without other systemic manifestations. We therefore conducted COL17A1 mutational analysis in three patients from two AI families. One nH-JEB patient showed no COL17A1 expression and was a compound heterozygote for the novel premature termination codon (PTC) mutations 1285delA and Q1387X. In addition, reduced COL17A1 expression was found in a second nH-JEB patient who was homozygous for the novel PTC mutation 4335delC, the most carboxyl terminal PTC mutation thus far identified. Due to nonsense mediated mRNA decay, the position of these PTC mutations is thought not to influence the effect of COL17A1 transcript loss and hence the severity of the nH-JEB phenotype. This study is the first to suggest that type XVII collagen carboxyl PTC mutations lead to restoration of truncated polypeptide expression and to a milder clinical disease severity in nH-JEB. Conversely, we failed to detect any pathogenic COL17A1 defects in AI patients, in either exon or within the intron-exon borders of AI patients. This study furthers the understanding of mutations in COL17A1 causing nH-JEB, and clearly demonstrates that the mechanism of enamel hypoplasia differs between nH-JEB and AI diseases.