FVH1

  • 文章类型: Journal Article
    人类中央凹是中央视网膜中的特殊凹坑结构。中心凹发育不全是指中心凹不完全发育的一种情况,它与视力不佳有关。常染色体显性遗传的孤立性中央凹发育不全(FVH1)是中央凹发育不全(FH)的罕见疾病,缺乏任何其他眼部表现。FVH1与PAX6基因中的低态突变有关,该基因编码序列特异性DNA结合转录因子,用于眼睛的形态发生和进化。我们报告了17例PAX6突变与FVH1或FH相关的无虹膜和角膜混浊患者的发现。有三个突变的病人,p.V78E,p.V83F和p.R128H,在配对结构域(CTS)的C端亚结构域中始终具有严重的FH。含有代表性PAX6结合位点的单个报道分子的荧光素酶测定表明,这些突变的转录活性显着降低,与p.G65Rfs*5的截短突变相当。p.P20S在配对结构域的N末端亚结构域的患者,并且在脯氨酸-丝氨酸-苏氨酸-富含结构域(PSTD)中具有p.N365K的患者具有轻度FH。同源结构域中p.Q255L的患者患有严重的FH。P20S和Q255L突变体不影响转录活性。突变体N365K具有保留的DNA结合活性,但转录活性降低,由于低的PSTD反式激活。这些发现表明,与FVH1相关的突变是DNA结合能力和转录活性之间功能差异的基础。我们得出的结论是,PAX6基因中的广泛突变不限于CST区域,并且是FVH1的原因。
    The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the PAX6 gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with PAX6 mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the PAX6 gene is not limited to the CST region and are responsible for FVH1.
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  • 文章类型: Case Reports
    目的:常染色体显性遗传性中央凹发育不全(FVH1)是一种与PAX6基因突变相关的罕见疾病。作为一个孤立的疾病实体,FVH1不包括眼部疾病,如无虹膜,小眼症,白化病,和色盲.然而,它仅包括孤立的中央凹发育不全和中央凹发育不全伴老年性白内障。本报告的目的是介绍我们在来自两个FVH1家庭的四名患者中的发现,这些患者没有可见的眼科黄斑异常。
    方法:回顾两个FVH1家族的医疗记录和PAX6基因突变的遗传确认。
    方法:眼底照片,光学相干层析成像(OCT)和OCT血管造影(OCTA)图像,并确定了裂隙灯眼前节的发现。确定PAX6基因的突变类型。
    结果:一名3岁女孩(患者1)有视力发育受损的体征和症状,没有其他视网膜异常OU。OCT图像显示一个浅的中央凹窝,OCTA显示中央凹无血管区的缺失。第二名患者(患者2)是一名6岁的女孩,患有单侧轻度白内障和浅中央凹OU。在她无症状的母亲(患者3)和外祖父(患者4)中发现了类似的浅中央凹凹陷。尽管虹膜和后眼底正常,所有FVH1患者均有性腺发育.PAX6基因的遗传检测显示,患者1具有新的杂合突变(p。Asn365Lys)作为从头突变,患者2、3和4具有新的杂合突变(p。Pro20Ser)。
    结论:PAX6基因杂合突变可导致FVH1出现接近正常的黄斑。FVH1很难诊断,但是对中央凹结构和脉管系统的详细观察,检测是否存在淋病,有助于识别FVH1患者。
    OBJECTIVE: Autosomal dominant foveal hypoplasia (FVH1) is a rare disorder associated with mutations in the PAX6 gene. As an isolated disease entity, FVH1 does not include ocular disorders such as aniridia, microphthalmia, albinism, and achromatopsia. However, it only includes isolated foveal hypoplasia and foveal hypoplasia with presenile cataract. The purpose of this report is to present our findings in four patients from two families with FVH1 without visible ophthalmic macular abnormalities.
    METHODS: A review of the medical records of two families with FVH1 and genetic confirmation of mutations in the PAX6 gene.
    METHODS: Fundus photographs, optical coherence tomographic (OCT) and OCT angiographic (OCTA) images, and slit-lamp anterior segment findings were determined. The type of mutation of the PAX6 gene was determined.
    RESULTS: A 3-year-old girl (Patient 1) had signs and symptoms of an impairment in the development of vision without other retinal abnormalities OU. OCT images showed a shallow foveal pit, and OCTA showed the absence of the foveal avascular zone. The second patient (Patient 2) was a 6-year-old girl with unilateral mild cataract and shallow foveal pits OU. Similar shallow foveal pits were found in her asymptomatic mother (Patient 3) and maternal grandfather (Patient 4). Although the iris and posterior fundus were normal, all patients with FVH1 had goniodysgenesis. Genetic testing of the PAX6 gene revealed that Patient 1 had a novel heterozygous mutation (p.Asn365Lys) as a de novo mutation, and Patients 2, 3 and 4 had a novel heterozygous mutation (p.Pro20Ser).
    CONCLUSIONS: Heterozygous mutations in the PAX6 gene can cause FVH1 with nearly normal appearing macula. FVH1 is difficult to diagnose, but detailed observations of the foveal structure and vasculature, and detecting the presence of goniodysgenesis can be helpful in identifying patients with FVH1.
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