FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.
FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.
复制标题
DOI：
10.1111/pedi.12612
复制
发表时间：
2018-05
影响因子：
3.4
通讯作者：
T2D-Genes Consortium
中科院分区：
文献类型：
--
作者：
Hwang JL;Park SY;Ye H;Sanyoura M;Pastore AN;Carmody D;Del Gaudio D;Wilson JF;Hanis CL;Liu X;Atzmon G;Glaser B;Philipson LH;Greeley SAW;T2D-Genes Consortium
糖尿病的发病率为1/9 - 1/16万，如果在6个月以下被诊断出来，很可能是由原发性遗传原因引起的。FOXP3编码一种对T调节细胞功能至关重要的转录因子，已知突变可导致“免疫失调、多内分泌病（包括需要胰岛素的糖尿病）、肠病、x连锁”（IPEX）综合征。这种情况通常是致命的，除非患者接受骨髓移植。在这里，我们描述了男性新生儿和没有其他IPEX综合征特征的需要胰岛素的糖尿病婴儿的表型，并发现FOXP3突变。在没有已知遗传原因的孤立新生儿糖尿病患者中，对感兴趣的基因进行了全外显子组或下一代测序。采用RT-PCR技术研究了一种新的内含子剪接位点变异对RNA剪接的影响。4名男性受试者在半合子状态下发现FOXP3变异：p.Arg114Trp, p.Arg347His, p.Lys393Met和c.1044+5G>A，在2个无关联先证和2.1岁诊断为糖尿病的兄弟中检测到。其中，p.a g114trp可能是在德系犹太人血统个体中发现的一种良性罕见变异，p.a g347his先前在经典IPEX综合征患者中被描述过。p.Lys393Met和c.1044+5G >a变体是本研究的新发现。对c.1044+5G>A剪接变异的RT-PCR研究证实，它通过产生野生型和截短转录物来影响RNA剪接。我们得出结论，FOXP3突变可导致伴或不伴IPEX综合征其他特征的早发性胰岛素需用糖尿病。
Diabetes occurs in 1/90,000–1/160,000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause “Immune dysregulation, Polyendocrinopathy (including insulin-requiring diabetes), Enteropathy, X-linked” (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.
登录
查看更多内容
影响因子：
5.6
作者：
Menon R;Deng M;Boehm D;Braun M;Fend F;Boehm D;Biskup S;Perner S
通讯作者：
Perner S
影响因子：
29.4
作者：
Moes, Nicolette;Rieux-Laucat, Frederic;Ruemmele, Frank M.
通讯作者：
Ruemmele, Frank M.
影响因子：
16.2
作者：
Rubio-Cabezas, Oscar;Minton, Jayne A. L.;Caswell, Richard;Shield, Julian P.;Deiss, Dorothee;Sumnik, Zdenek;Cayssials, Amely;Herr, Mathias;Loew, Anja;Lewis, Vaughan;Ellard, Sian;Hattersley, Andrew T.
通讯作者：
Hattersley, Andrew T.
影响因子：
30.8
作者：
Wildin, RS;Ramsdell, F;Brunkow, ME
通讯作者：
Brunkow, ME
影响因子：
1.4
作者：
Alkorta-Aranburu, Gorka;Sukhanova, Madina;del Gaudio, Daniela
通讯作者：
del Gaudio, Daniela