Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes
Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes
复制标题
儿童期 1A 型糖尿病中 PTPN2 的蛋白质改变变异
DOI：
10.1111/dme.13566
复制
发表时间：
2018
影响因子：
3.5
通讯作者：
the Japanese Study Group of Insulin Therapy
中科院分区：
文献类型：
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作者：
Okuno M.;Ayabe T.;Yokota I.;Musha I.;Shiga K.;Kikuchi T.;Kikuchi N.;Ohtake A.;Nakamura A.;Nakabayashi K.;Okamura K.;Momozawa Y.;Kubo M.;Suzuki J.;Urakami T.;Kawamura T.;Amemiya S.;Ogata T.;Sugihara S.;Fukami M.;the Japanese Study Group of Insulin Therapy
目的研究PTPN 2编码变异对儿童期发病的1A型糖尿病风险的贡献。方法对169例无血缘关系的日本儿童期发病的1A型糖尿病患者进行PTPN 2突变分析。我们搜索了在普通人群中不存在或极其罕见的编码变异，并通过多个计算机程序进行了破坏性评分。如果可能，我们对检测到的变体进行了mRNA分析和三维结构预测。我们还研究了这些变异体和以前报道的风险SNPs之间可能的物理联系，以及变异阳性children.ResultsOne移码变异（p.Q286Yfs*24）和两个可能具有破坏性的错义替换（p.C232W和p.R350Q）在一个孩子中被确定。其中，p.Q286Yfs*24和p.C232W迄今未报道，而p.R350Q占外显子组数据集的2/121，122等位基因。p.Q286Yfs*24变体不编码稳定的mRNA，而p.C232W似乎影响酪氨酸蛋白磷酸酶结构域的结构。这三种变异与已知的风险SNP在物理上无关。PTPN 2变异阳性的儿童表现为1A型糖尿病，没有额外的临床特征，并且总是携带危险的人类白细胞抗原等位基因.ConclusionsThe results provide the first indications that PTPN 2 variants contribute to the risk of Type 1A diabetes，independently of known risk SNPs. PTPN 2编码变异可能在人类白细胞抗原介导的疾病易感性个体中诱导非特异性1A型糖尿病表型。我们的发现值得进一步验证。
AimTo examine the contribution of PTPN2 coding variants to the risk of childhood‐onset Type 1A diabetes.MethodsPTPN2mutation analysis was carried out for 169 unrelated Japanese people with childhood‐onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiplein silicoprograms. We performed mRNA analysis and three‐dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant‐positive children.ResultsOne frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine‐protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant‐positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles.ConclusionsThe results provide the first indication thatPTPN2variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs.PTPN2coding variants possibly induce non‐specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen‐mediated disease susceptibility. Our findings warrant further validation.