Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Ophthalmology. 2013 Dec;120(12):2697-2705. doi: 10.1016/j.ophtha.2013.07.052. Epub 2013 Sep 29.
Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness and peripheral vision loss, and in many cases leads to blindness. Despite extensive knowledge about genes involved in the pathogenesis of RP, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the cause of RP.
We present a case series with mutations in the mevalonate kinase (MVK) gene.
A total of 769 patients with nonsyndromic RP and 174 Dutch control individuals participated in this study.
Exome sequencing analysis was performed in a proband of Dutch origin who was initially diagnosed with nonsyndromic autosomal recessive RP. Mutations in MVK were identified and subsequently tested for segregation within the patient's family and screened in a large cohort of patients with genetically unsolved RP. Patients with mutations underwent extensive clinical reexamination.
Digital fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence analysis were performed in patients with MVK mutations. Mevalonate kinase (MK) enzyme activity was analyzed in cultured lymphoblastoid cells, and mevalonic acid levels were measured in urine samples.
Exome variant filtering and prioritization led to the identification of compound heterozygous mutations in MVK (p.I268T and p.A334T) in the proband and her affected brother. Screening of our nonsyndromic RP patient cohort revealed an additional individual who was homozygous for the p.A334T alteration. Clinical reevaluation of all 3 patients showed a classic form of RP with variable extraocular symptoms, such as history of recurrent childhood febrile crises in 2 patients, mild ataxia in 1, and renal failure in 1. All 3 affected individuals showed a significantly decreased MK activity and highly elevated levels of urinary mevalonic acid.
Although the MK activity in cells and mevalonic acid concentrations in urine are strongly aberrant and comparable to that in patients with systemic mevalonate kinase deficiency (MKD), only mild clinical symptoms related to this syndrome were observed in our patients. In the current article, we add another phenotype to the spectrum of diverging disorders associated with mutations in MVK.
色素性视网膜炎（RP）是一种临床表现和遗传异质性疾病，其特征为夜盲和周边视野丧失，且在许多情况下会导致失明。尽管人们对参与 RP 发病机制的基因有广泛的了解，但在许多患者中，遗传病因仍难以确定。在本研究中，我们旨在鉴定参与 RP 发病的新基因。
我们呈现了一系列携带甲羟戊酸激酶（MVK）基因突变的病例。
共有 769 名非综合征性 RP 患者和 174 名荷兰对照个体参与了这项研究。
对一名最初被诊断为非综合征性常染色体隐性 RP 的荷兰血统先证者进行外显子组测序分析。鉴定 MVK 中的突变，并随后在患者的家系内进行分离检验，以及在遗传原因不明的大量 RP 患者队列中进行筛查。对携带突变的患者进行广泛的临床重新检查。
对携带 MVK 突变的患者进行数字眼底摄影、光谱域光学相干断层扫描（OCT）和眼底自发荧光分析。对培养的淋巴母细胞系中的甲羟戊酸激酶（MK）酶活性进行分析，并测量尿液样本中的甲羟戊酸水平。
外显子变异过滤和优先级排序导致在先证者及其受影响的兄弟中鉴定出 MVK（p.I268T 和 p.A334T）的复合杂合突变。对我们的非综合征性 RP 患者队列进行筛查发现，另一名个体为 p.A334T 改变的纯合子。对所有 3 名患者的临床重新评估显示出典型的 RP 形式，具有不同的眼外症状，如 2 名患者有复发性儿童发热性危象的病史、1 名患者有轻度共济失调、1 名患者有肾衰竭。所有 3 名受影响的个体的 MK 活性显著降低，尿液中甲羟戊酸水平显著升高。
尽管细胞中的 MK 活性和尿液中的甲羟戊酸浓度严重异常，且与全身性甲羟戊酸激酶缺乏症（MKD）患者的相似，但我们的患者仅观察到与该综合征相关的轻度临床症状。在本文中，我们为 MVK 突变相关的不同疾病谱增加了另一种表型。
