Roos Laura, Bertelsen Birgitte, Harris Pernille, Bygum Anette, Jensen Hanne, Grønskov Karen, Tümer Zeynep
Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, 2600, Denmark.
Department of Chemistry, Technical University of Denmark, Kemitorvet Build. 207, DK-2800, Kgs. Lyngby, Denmark.
BMC Med Genet. 2015 Jun 23;16:40. doi: 10.1186/s12881-015-0179-9.
Cornea plana (CNA) is a hereditary congenital abnormality of the cornea characterized by reduced corneal curvature, extreme hypermetropia, corneal clouding and hazy corneal limbus. The recessive form, CNA2, is associated with homozygous or compound heterozygous mutations of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described.
In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation is predicted to destabilize the structure of keratocan, leading to the classical ocular phenotype in the affected individuals. All the four known missense mutations, including the variation found in this family, affect the conserved residues of the leucine rich repeat domain of keratocan. These mutations are predicted to result in destabilization of the protein.
We present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function, and this knowledge will ease the interpretation of future findings of mutations in these areas in other families with cornea plana.
扁平角膜（CNA）是一种遗传性先天性角膜异常，其特征为角膜曲率降低、高度远视、角膜混浊和角膜缘模糊。隐性形式的CNA2与12q22染色体上的角蛋白聚糖基因（KERA）的纯合或复合杂合突变相关。迄今为止，仅描述了9种不同的与疾病相关的KERA突变，包括4种错义突变。
在本报告中，我们展示了一个患有常染色体隐性扁平角膜的土耳其家庭的临床数据。在一些受影响个体中发现了毛发稀少。使用桑格测序法对KERA进行突变筛查。我们检测到一种新的KERA变异体p.(Ile225Thr)，它以纯合形式与疾病共分离。对角蛋白聚糖蛋白的三维结构进行了建模，我们发现这种错义变异预计会破坏角蛋白聚糖的结构，导致受影响个体出现典型的眼部表型。所有4种已知的错义突变，包括在这个家庭中发现的变异，都影响角蛋白聚糖富含亮氨酸重复结构域的保守残基。这些突变预计会导致蛋白质不稳定。
我们展示了迄今为止鉴定出的第10种致病性KERA突变。蛋白质建模是预测错义突变影响的有用工具。该病例强调了富含亮氨酸重复结构域对蛋白质功能的重要性，这一知识将有助于解释未来在其他扁平角膜家庭中这些区域突变的发现。
