Reduced penetrance in familial Avellino corneal dystrophy associated with TGFBI mutations
Reduced penetrance in familial Avellino corneal dystrophy associated with TGFBI mutations
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DOI：
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发表时间：
2009-01
期刊：
影响因子：
2.2
通讯作者：
W. Cao;H. Ge;X. Cui;Lu Zhang;J. Bai;Song-bin Fu;Ping Liu
中科院分区：
文献类型：
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作者：
W. Cao;H. Ge;X. Cui;Lu Zhang;J. Bai;Song-bin Fu;Ping Liu
目的探讨Avellino角膜营养不良(ACD)家系的临床表型、组织病理学特征和分子遗传学基础。方法对该家系21人(6人患病，15人未患病)进行全面的眼科检查。从每个受试者的外周血白细胞中提取DNA。遗传分析包括TGFBI聚合酶链式反应(PCR)扩增和基因组DNA全部17个外显子的自动核苷酸测序。穿透性角膜移植后对先证者的角膜组织进行组织学分析。通过扩增TGFBI外显子4，然后对PCR产物进行直接测序，对100名中国人进行了R124H突变的扫描。结果该家系先证者具有与ACD诊断一致的表型特征。他在TGFBI中存在与之前在日本和欧洲国家报道的相同的R124H突变纯合子。此外，还鉴定了4个受影响个体和7个未受影响个体在杂合子状态中携带相同的变异。在100名对照受试者中，没有一人对该突变呈阳性。此外，在我们的家系中观察到杂合子R124H突变的个体具有不同的表现力和明显的非外显性。排除漏诊或发病较晚后，可将其解释为外显率降低。结论我们报道了一个新的中国北部ACD家系，其表型外显性降低。这一结果支持虽然R124H突变是该病的遗传原因之一，但不同的遗传和环境因素可能会影响该基因的表达和外显性。无论是纯合子突变还是杂合子突变，揭示TGFBI中R124H突变引起的角膜营养不良的发生机制都可能有助于我们抑制TGFBI中R124H突变引起的角膜营养不良的发生。
Purpose To characterize the clinical phenotype, histopathological features, and molecular genetic basis of an Avellino corneal dystrophy (ACD) in a Chinese family. Methods A complete ophthalmologic examination was performed in 21 individuals (6 affected and 15 unaffected) of the four-generation family. DNA was obtained from peripheral blood leukocytes of each participant. Genetic analysis included TGFBI polymerase chain reaction (PCR) amplification and automated nucleotidic sequenceing of all 17 exons of genomic DNA. Histological analysis of corneal tissue from the proband was performed after a penetrating keratoplasty. One hundred Chinese controls were scanned for the presence of the R124H mutation by amplifying TGFBI exon 4 and then by direct sequencing of PCR products. Results The proband of the pedigree had phenotypic features consistent with diagnosis of ACD. He was homozygous for the same R124H mutation in TGFBI as previously reported in Japan and European countries. In addition, 4 affected and 7 unaffected individuals carried the same variation in the heterozygous state were identified. None of the 100 control subjects was positive for this mutation. Moreover, a variable expressivity and an apparent non-penetrance were observed in the individuals with heterozygous R124H mutation in our pedigree. After excluding the missed diagnosis or a late onset, it could be interpreted as a reduced penetrance. Conclusions We reported a novel ACD family which exhibited a reduced penetrance of phenotype in northern China. This outcome supports that although the R124H mutation is one of the genetic causes of the disease, different genetic and environmental factors may influence the expressivity and the penetrance. Uncovering the mechanism may facilitate us to inhibit the occurrence of the corneal dystrophy caused by the R124H mutation in TGFBI, irrespective of the homozygous and heterozygous mutation.