Genotype-phenotype correlation in primary carnitine deficiency.
Genotype-phenotype correlation in primary carnitine deficiency.
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DOI：
10.1002/humu.21607
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发表时间：
2012-01
期刊：
影响因子：
3.9
通讯作者：
Longo, Nicola
中科院分区：
文献类型：
--
作者：
Rose, Emily C.;di San Filippo, Cristina Amat;Erlingsson, Uzochi C. Ndukwe;Ardon, Orly;Pasquali, Marzia;Longo, Nicola
原发性肉碱缺乏是由SLC22A5基因编码的OCTN2肉碱转运体缺陷引起的。缺乏肉碱会损害脂肪酸的氧化，导致低酮低血糖、肝性脑病、骨骼肌和心肌病。最近，通过新生儿筛查发现，患有原发性肉碱缺乏的无症状母亲的婴儿肉碱水平较低。在这里，我们评估了SLC22A5基因突变和肉碱在有症状患者和无症状女性成纤维细胞中的转运。所有原发性肉碱缺乏症患者的成纤维细胞的肉碱转运均显著降低，但无症状患者的肉碱转运显著高于有症状患者的成纤维细胞(p<；0.01)。相比之下，麦角硫蛋白转运(OCTN1转运蛋白的一种选择性底物，在这里测试为对照)在对照组和肉碱缺乏症患者的细胞中相似。DNA测序表明，在有症状的患者中，无义突变的频率增加(p<；0.001)。错义突变在CHO细胞中的表达表明，许多突变保留了残留的肉碱转运活性，而在有症状和无症状患者中发现的错义突变的平均活性没有差异。这些结果表明，与有症状的患者相比，无症状女性的细胞平均具有更高水平的残留肉碱转运活性，这是因为至少存在一个错义突变。
Primary carnitine deficiency is caused by defective OCTN2 carnitine transporters encoded by the SLC22A5 gene. Lack of carnitine impairs fatty acid oxidation resulting in hypoketotic hypoglycemia, hepatic encephalopathy, skeletal and cardiac myopathy. Recently, asymptomatic mothers with primary carnitine deficiency were identified by low carnitine levels in their infant by newborn screening. Here we evaluate mutations in the SLC22A5 gene and carnitine transport in fibroblasts from symptomatic patients and asymptomatic women. Carnitine transport was significantly reduced in fibroblasts obtained from all patients with primary carnitine deficiency, but was significantly higher in the asymptomatic women’s than in the symptomatic patients’ fibroblasts (p<0.01). By contrast, ergothioneine transport (a selective substrate of the OCTN1 transporter, tested here as a control) was similar in cells from controls and patients with carnitine deficiency. DNA sequencing indicated an increased frequency of nonsense mutations in symptomatic patients (p<0.001). Expression of the missense mutations in CHO cells indicated that many mutations retained residual carnitine transport activity, with no difference in the average activity of missense mutations identified in symptomatic versus asymptomatic patients. These results indicate that cells from asymptomatic women have on average higher levels of residual carnitine transport activity as compared to that of symptomatic patients due to the presence of at least one missense mutation.
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影响因子：
3.5
作者：
Tang, NLS;Ganapathy, V;Hjelm, NM
通讯作者：
Hjelm, NM
影响因子：
4.8
作者：
di San Filippo, CA;Wang, YH;Longo, N
通讯作者：
Longo, N
影响因子：
3.9
作者：
Dobrowolski, SE;McKinney, JT;Longo, N
通讯作者：
Longo, N
影响因子：
--
作者：
LONGO, N;GRIFFIN, LD;ELSAS, LJ
通讯作者：
ELSAS, LJ
影响因子：
4.2
作者：
Lund, A. M.;Joensen, F.;Skovby, F.
通讯作者：
Skovby, F.