Manimaran Paramasivam, Subramanian Veedamali S, Karthi Sellamuthu, Gandhimathi Krishnan, Varalakshmi Perumal, Ganesh Ramasamy, Rathinavel Andiappan, Said Hamid M, Ashokkumar Balasubramaniem
School of Biotechnology, Madurai Kamaraj University, Madurai 625 021, India.
Departments of Medicine, Physiology/Biophysics, University of California, Irvine, CA; Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
Clin Chim Acta. 2016 Jan 15;452:44-9. doi: 10.1016/j.cca.2015.11.002. Epub 2015 Nov 5.
Thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive disorder, is caused by mutations in SLC19A2 gene encodes a high affinity thiamine transporter (THTR-1). The occurrence of TRMA is diagnosed by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Here, we report a female TRMA patient of Indian descent born to 4th degree consanguineous parents presented with retinitis pigmentosa and vision impairment, who had a novel homozygous mutation (c.1232delT/ter422; p.Ile411Metfs12) in 5th exon of SLC19A2 gene that causes premature termination of hTHTR-1. PROSITE analysis predicted to abrogate GPCRs family-1 signature motif in the variant by this mutation c.1232delT/ter422, suggesting uncharacteristic rhodopsin function leading to cause RP clinically. Thiamine transport activity by the clinical variant was severely inhibited than wild-type THTR-1. Confocal imaging had shown that the variant p.I411Mfs12 is targeted to the cell membrane and showed no discrepancy in membrane expression than wild-type. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of hTHTR-1 causing TRMA in an Indian patient through functionally impaired thiamine transporter activity.
硫胺素反应性巨幼细胞贫血（TRMA）是一种常染色体隐性疾病，由编码高亲和力硫胺素转运蛋白（THTR-1）的SLC19A2基因突变引起。TRMA的诊断依据为巨幼细胞贫血、糖尿病和感音神经性耳聋。在此，我们报告一名印度裔女性TRMA患者，其父母为四代近亲结婚，该患者患有视网膜色素变性和视力损害，其SLC19A2基因第5外显子存在一个新的纯合突变（c.1232delT/ter422；p.Ile411Metfs12），导致hTHTR-1提前终止。PROSITE分析预测，该c.1232delT/ter422突变会消除该变体中的GPCRs家族1特征基序，提示视紫红质功能异常，临床上导致视网膜色素变性。与野生型THTR-1相比，该临床变体的硫胺素转运活性受到严重抑制。共聚焦成像显示，变体p.I411Mfs12定位于细胞膜，与野生型相比，膜表达无差异。据我们所知，我们的研究结果是关于hTHTR-1这种新的无义突变通过硫胺素转运蛋白活性受损导致一名印度患者患TRMA的首次报道。
