Survey of patients with granular, lattice, avellino, and Reis-Bücklers corneal dystrophies for mutations in the BIGH3 and gelsolin genes.
Survey of patients with granular, lattice, avellino, and Reis-Bücklers corneal dystrophies for mutations in the BIGH3 and gelsolin genes.
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发表时间：
2001
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通讯作者：
Nasrin A. Afshari;J. Mullally;Mehran A. Afshari;R. Steinert;A. Adamis;D. Azar;J. Talamo;C. Dohlman;T. Dryja
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作者：
Nasrin A. Afshari;J. Mullally;Mehran A. Afshari;R. Steinert;A. Adamis;D. Azar;J. Talamo;C. Dohlman;T. Dryja
目的寻找导致角膜基质营养不良的新基因突变，以确认或修订这些突变患者的临床诊断。患者通过查阅波士顿马萨诸塞州眼耳医院Cogan眼科病理实验室的记录和临床记录，我们确定了14例临床或组织病理诊断为颗粒状(3例)、Avellino(5例)、晶格(5例)或Reis-Bück ler(1例)角膜营养不良的患者。方法回顾分析本组病例及其亲属的临床资料和病理组织学表现。患者和选定的亲属捐献了一份血液样本，从中提纯了白细胞DNA，并使用聚合酶链式反应和直接基因组测序对BIGH3基因和2名患者的明胶蛋白基因的突变进行了分析。结果所有诊断为颗粒性营养不良或Avellino营养不良的指标患者均存在BIGH3基因错义突变Arg555Trp或Arg124His。在5例既往诊断为晶格型营养不良的患者中，2例为BIGH3基因的晶格突变(Arg124Cys)，1例为最近报道的同一基因的错义突变(His626Arg)，1例为明胶蛋白基因的错义突变Asp187Asn，1例均未检测到突变。受影响的Reis-Büockler营养不良家族成员没有携带先前报道的Arg555Gln或Arg124Leu突变，而是在BIGH3基因中携带一种新的错义突变Gly623Asp。结论分子遗传学分析可提高角膜营养不良患者的诊断准确率。2例先前诊断为晶格状角膜营养不良的患者被诊断为明胶蛋白相关性淀粉样变性(1例)或继发性非遗传性局限性淀粉样变性(1例)。通过这一分析发现了导致Reis-Büockler营养不良的BIGH3基因的一个新突变，并遇到了另一个最近报道的新突变。这些发现有助于扩大我们对BIGH3致病突变谱的了解。
OBJECTIVES To search for novel mutations that cause corneal stromal dystrophies and to confirm or revise the clinical diagnosis of patients with these mutations. PATIENTS Through review of the records of the Cogan Eye Pathology Laboratory at the Massachusetts Eye and Ear Infirmary, Boston, and of clinical records, we ascertained 14 unrelated patients with the clinical or histopathologic diagnosis of granular (3 cases), Avellino (5 cases), lattice (5 cases), or Reis-Bücklers (1 case) corneal dystrophy. METHODS Clinical records and histopathologic findings of the index patients and their relatives were reviewed. Patients and selected relatives donated a blood sample from which leukocyte DNA was purified and assayed for mutations in the BIGH3 gene and, in 2 patients, the gelsolin gene, using the polymerase chain reaction and direct genomic sequencing. RESULTS All index patients with the diagnosis of granular dystrophy or Avellino dystrophy had the missense mutation Arg555Trp or Arg124His, respectively, previously reported in the BIGH3 gene. Of the 5 index patients with a prior diagnosis of lattice dystrophy, 2 had the originally reported lattice mutation (Arg124Cys) in the BIGH3 gene, 1 had a more recently reported missense mutation (His626Arg) in the same gene, 1 had the missense mutation Asp187Asn in the gelsolin gene, and 1 had no detected mutation in either gene. Affected members of the family with Reis-Bücklers dystrophy did not carry the previously reported mutations Arg555Gln or Arg124Leu but instead carried a novel missense mutation Gly623Asp in the BIGH3 gene. CONCLUSIONS Molecular genetic analysis can improve the accuracy of diagnosis of patients with corneal dystrophies. Two patients with a prior diagnosis of lattice corneal dystrophy had their diagnosis changed to gelsolin-related amyloidosis (1 case) or secondary, nonhereditary localized amyloidosis (1 case). A novel mutation in the BIGH3 gene that causes Reis-Bücklers dystrophy was uncovered through this analysis, and another recently reported novel mutation was encountered. These findings serve to expand our knowledge of the spectrum of pathogenic mutations in BIGH3.