Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Ophthalmology. 2013 Jun;120(6):1239-46. doi: 10.1016/j.ophtha.2012.12.005. Epub 2013 Mar 15.
The majority of the genetic causes of autosomal recessive (ar) cone dystrophy (CD) and cone-rod dystrophy (CRD) are currently unknown. We used a high-resolution homozygosity mapping approach in a cohort of patients with CD or CRD to identify new genes for ar cone disorders.
Case series.
A cohort of 159 patients with ar CD and 91 patients with CRD.
The genomes of 83 patients with ar CD and 73 patients with CRD were analyzed for homozygous regions using single nucleotide polymorphism (SNP) microarrays. One patient showed homozygosity of SNPs across chromosome 6, and segregation analysis was performed using microsatellite markers. Direct sequencing of all retinal disease genes on chromosome 6 revealed a novel pathogenic TULP1 mutation in this patient. A cohort of 159 individuals with CD and 91 individuals with CRD was screened for this particular mutation using the restriction enzyme HhaI. The medical history of patients carrying the TULP1 mutation was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence (FAF), and fundus photography.
TULP1 mutations, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, FAF, and OCT findings.
In 1 patient, homozygosity mapping and subsequent segregation analysis revealed maternal uniparental disomy (UPD) of chromosome 6. A novel homozygous missense mutation (p.Arg420Ser) was identified in TULP1, whereas no mutations were detected in other retinal disease genes on chromosome 6. The mutation affects a highly conserved amino acid residue in the Tubby domain and is predicted to be pathogenic. The same homozygous mutation was also identified in an additional, unrelated patient with CRD. Both patients carrying the p.Arg420Ser mutation presented with a bull's eye maculopathy. The first patient had progressive loss of visual acuity with a relatively preserved ERG, whereas the second patient developed loss of visual acuity, peripheral degeneration, and severely reduced ERG responses in a cone-rod pattern.
Maternal UPD of chromosome 6 unmasked a mutation in the TULP1 gene as a novel cause of cone dysfunction. This expands the disease spectrum of TULP1 mutations from Leber congenital amaurosis and early-onset retinitis pigmentosa to cone-dominated disease.
FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
常染色体隐性（ar） cones 变性（CD）和 cones-rod 变性（CRD）的大多数遗传原因目前尚不清楚。我们使用 CD 或 CRD 患者队列中的高分辨率纯合性作图方法来鉴定 ar cones 疾病的新基因。
病例系列。
ar CD 患者 159 例，CRD 患者 91 例。
使用单核苷酸多态性（SNP）微阵列分析 83 例 ar CD 患者和 73 例 CRD 患者的基因组中纯合区域。一位患者的染色体 6 上的 SNP 出现纯合性，使用微卫星标记进行分离分析。该患者的染色体 6 上所有视网膜疾病基因的直接测序显示出一种新的致病性 TULP1 突变。使用限制酶 HhaI 对 159 例 CD 患者和 91 例 CRD 患者进行了该特定突变的筛查。对携带 TULP1 突变的患者的病史进行了回顾，并进行了额外的眼科检查，包括视网膜电图（ERG）、视野检查、光学相干断层扫描（OCT）、眼底自发荧光（FAF）和眼底照相。
TULP1 突变、诊断年龄、视力、眼底外观、色觉缺陷、视野、ERG、FAF 和 OCT 结果。
在 1 例患者中，纯合性作图和随后的分离分析显示 6 号染色体母系单亲二倍体（UPD）。在 TULP1 中发现了一种新的纯合错义突变（p.Arg420Ser），而 6 号染色体上的其他视网膜疾病基因未发现突变。该突变影响 Tubby 结构域中高度保守的氨基酸残基，预计具有致病性。另一位患有 CRD 的无关患者也发现了相同的纯合突变。携带 p.Arg420Ser 突变的两位患者均表现为靶心状黄斑病变。第一例患者视力逐渐丧失，ERG 相对保留，而第二例患者视力丧失、周边变性和严重降低的 cone-rod 模式 ERG 反应。
6 号染色体的母系 UPD 揭示了 TULP1 基因中的突变是 cones 功能障碍的一个新原因。这将 TULP1 突变的疾病谱从 Leber 先天性黑朦和早发性视网膜色素变性扩展到以 cones 为主的疾病。
作者没有与本文讨论的任何材料有关的专有或商业利益。
