Functional and molecular studies in primary carnitine deficiency.
Functional and molecular studies in primary carnitine deficiency.
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DOI：
10.1002/humu.23315
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发表时间：
2017-12
期刊：
影响因子：
3.9
通讯作者：
Longo N
中科院分区：
文献类型：
--
作者：
Frigeni M;Balakrishnan B;Yin X;Calderon FRO;Mao R;Pasquali M;Longo N
原发性肉毒碱缺乏是由SLC22A5基因编码的OCTN2肉毒碱转运体缺陷引起的。它可引起儿童低酮性低血糖症或心肌病，以及儿童和成人猝死。来自受影响患者的成纤维细胞减少了肉碱运输。我们评估了358名可能缺乏肉毒碱的受试者成纤维细胞中的肉毒碱转运。140/358名受试者的成纤维细胞中肉碱转运减少到正常水平的20%或更少。对95/140名受试者的SLC22A5基因的10个外显子和侧翼区域进行测序，发现84%的等位基因存在致病变异。在我们的患者和其他先前报道的患者（n=92）中发现的错义变异在CHO细胞中表达。表达的73/92个变异抑制了肉毒碱的转运。预测算法（polyphen2， SIFT）在约80%的病例中正确预测了表达变异的功能影响。这些结果表明，在引起原发性肉毒碱缺乏症的等位基因中，约有16%的SLC22A5基因编码区无法识别突变。在大约20%的情况下，预测算法无法确定氨基酸取代对这种跨膜蛋白的功能影响。因此，成纤维细胞的功能研究仍然是确认或排除原发性肉碱缺乏症诊断的最佳策略。
Primary carnitine deficiency is caused by a defect in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. It can cause hypoketotic hypoglycemia or cardiomyopathy in children, and sudden death in children and adults. Fibroblasts from affected patients have reduced carnitine transport. We evaluated carnitine transport in fibroblasts from 358 subjects referred for possible carnitine deficiency. Carnitine transport was reduced to 20% or less of normal in fibroblasts of 140/358 subjects. Sequencing of the 10 exons and flanking regions of the SLC22A5 gene in 95/140 subjects identified causative variants in 84% of the alleles. The missense variants identified in our patients and others previously reported (n=92) were expressed in CHO cells. Carnitine transport was impaired by 73/92 variants expressed. Prediction algorithms (Polyphen-2, SIFT) correctly predicted the functional effects of expressed variants in about 80% of cases. These results indicate that mutations in the coding region of the SLC22A5 gene cannot be identified in about 16% of the alleles causing primary carnitine deficiency. Prediction algorithms failed to determine the functional effects of amino acid substitutions in this transmembrane proteins in about 20% of cases. Therefore, functional studies in fibroblasts remain the best strategy to confirm or exclude a diagnosis of primary carnitine deficiency.
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DOI：
10.1007/8904_2011_52
发表时间：
2012-01-01
期刊：
JIMD REPORTS - CASE AND RESEARCH REPORTS, 2011/2
影响因子：
--
作者：
De Biase, Irene;Champaigne, Neena Lorenzana;Wood, Tim
通讯作者：
Wood, Tim
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：
3.9
作者：
Filippo, Cristina Amat di San;Pasquali, Marzia;Longo, Nicola
通讯作者：
Longo, Nicola
影响因子：
4.2
作者：
Komlosi, K.;Magyari, L.;Melegh, B.
通讯作者：
Melegh, B.