Brittle Cornea Syndrome Associated with a Missense Mutation in the Zinc-Finger 469 Gene
Brittle Cornea Syndrome Associated with a Missense Mutation in the Zinc-Finger 469 Gene
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DOI：
10.1167/iovs.09-4251
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发表时间：
2010-01-01
影响因子：
4.4
通讯作者：
Boman, Helge
中科院分区：
文献类型：
--
作者：
Christensen, Anne E.;Knappskog, Per M.;Boman, Helge
目的.研究脆性角膜综合征（BCS）家系的临床表现，确定致病突变，并解释其与红头发的关系。三代中的八名家庭成员接受了眼科、牙科和一般医学检查，包括脊柱放射学检查。测量骨密度（BMD）和血清维生素D、甲状旁腺激素和骨转换生化标志物水平。通过光镜和透射电镜检查皮肤活检。分子遗传学研究包括SNP标记的纯合性作图、DNA测序和MC 1 R基因分型。在42岁和48岁时，两个受影响的个体分别由于视网膜脱离和继发性青光眼而失明。他们的角膜非常薄且凸出，皮肤光滑，栗色的头发，脊柱侧凸，骨密度降低，牙齿畸形，听力丧失和轻微的心脏缺陷。皮肤活检的形态是正常的，除了在某些地区略薄的胶原纤维被视为在一个受影响的个人。分子遗传学分析发现ZNF 469基因存在一个新的错义突变，即c. 10016 G>A，其被预测通过将第一个半胱氨酸改变为酪氨酸（p.Cys3339Tyr）来影响ZNF 469的五个锌指结构域中的第四个。这两个受影响的个人是纯合子的共同红头发变异R151 C在MC 1 R基因座。BCS是一种影响多种结缔组织的疾病。BMD降低和非典型牙冠形态以前没有报道过。结果证实BCS与ZNF 469突变相关。在某些BCS患者中与红头发的关联可能是偶然发生的。（Invest Ophthalmol维斯科学。2010; 51：47-52）DOI：10.1167/iovs.09-4251
PURPOSE. To investigate the diverse clinical manifestations, identify the causative mutation and explain the association with red hair in a family with brittle cornea syndrome (BCS).METHODS. Eight family members in three generations underwent ophthalmic, dental, and general medical examinations, including radiologic examination of the spine. Bone mineral density (BMD) and serum levels of vitamin D, parathyroid hormone, and biochemical markers for bone turnover were measured. Skin biopsies were examined by light and transmission electron microscopy. Molecular genetic studies included homozygosity mapping with SNP markers, DNA sequencing, and MC1R genotyping.RESULTS. At 42 and 48 years of age, respectively, both affected individuals were blind due to retinal detachment and secondary glaucoma. They had extremely thin and bulging corneas, velvety skin, chestnut colored hair, scoliosis, reduced BMD, dental anomalies, hearing loss, and minor cardiac defects. The morphologies of the skin biopsies were normal except that in some areas slightly thinner collagen fibrils were seen in one of the affected individuals. Molecular genetic analysis revealed a novel missense mutation of ZNF469, c. 10016G>A, that was predicted to affect the fourth of the five zinc finger domains of ZNF469 by changing the first cysteine to a tyrosine (p. Cys3339Tyr). Both affected individuals were homozygous for the common red hair variant R151C at the MC1R locus.CONCLUSIONS. BCS is a disorder that affects a variety of connective tissues. Reduced BMD and atypical dental crown morphology have not been reported previously. The results confirm that BCS is associated with mutations in ZNF469. The association with red hair in some individuals with BCS is likely to occur by chance. (Invest Ophthalmol Vis Sci. 2010; 51: 47-52) DOI: 10.1167/iovs.09-4251