Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.
Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.
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DOI：
10.1371/journal.pone.0106906
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Tanizawa Y
中科院分区：
文献类型：
--
作者：
Matsunaga K;Tanabe K;Inoue H;Okuya S;Ohta Y;Akiyama M;Taguchi A;Kora Y;Okayama N;Yamada Y;Wada Y;Amemiya S;Sugihara S;Nakao Y;Oka Y;Tanizawa Y
Wolfram综合征(WFS)是一种隐性神经和内分泌退行性疾病，又称DIDMOAD(糖尿病尿崩症，早发性糖尿病，进行性视神经萎缩和耳聋)综合征。大多数受影响的人携带Wolfram综合征1基因(WFS1)的隐性突变。然而，这种疾病的表型多形性、稀有性和分子复杂性使我们对WFS的理解复杂化。为了解决这一局限性，我们旨在描述WFS1突变对日本WFS患者临床表现的影响，并描述WFS1突变的并发症。诊断WFS的最低确证标准是既有早发性糖尿病又有双侧视神经萎缩。用直接测序的方法对WFS1基因进行分析。在全国范围内确定了67名患者，其患病率为每710,000人中有一人，其中33名患者(49%)具有DIDMOAD的所有4个组成部分。在来自30个无血缘关系家庭的40名受试者中，最早的表现是糖尿病，中位年龄为8.7岁，其次是骨性关节炎，中位年龄为15.8岁。然而，在6名受试者中，OA或DI是第一个被诊断的特征。在10个病例中，DM以外的其他特征早于OA。27名患者(67.5%)在WFS1有广泛的隐性突变。两名患者只有一个等位基因发生突变。11例(27.5%)WFS1等位基因完整。WFS1隐性突变患者的糖尿病和骨性关节炎的发病年龄与无WFS1突变的患者无明显差别。在预测的功能完全丧失突变的患者中，糖尿病和骨性关节炎的发病年龄明显早于预测的部分功能突变的患者。这项研究强调了WFS患者的临床和遗传异质性。WFS1基因突变的患者可能存在基因-表型相关性，如疾病发病所证明的那样。
Wolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.
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影响因子：
30.8
作者：
Inoue, H;Tanizawa, Y;Permutt, MA
通讯作者：
Permutt, MA
影响因子：
8.2
作者：
Akiyama, M.;Hatanaka, M.;Tanizawa, Y.
通讯作者：
Tanizawa, Y.
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
16.2
作者：
d'Annunzio G;Minuto N;D'Amato E;de Toni T;Lombardo F;Pasquali L;Lorini R
通讯作者：
Lorini R
影响因子：
8.2
作者：
Franks, P. W.;Rolandsson, O.;Debenham, S. L.;Fawcett, K. A.;Payne, F.;Dina, C.;Froguel, P.;Mohlke, K. L.;Willer, C.;Olsson, T.;Wareham, N. J.;Hallmans, G.;Barroso, I.;Sandhu, M. S.
通讯作者：
Sandhu, M. S.