Department of Biotechnology and Genetic Engineering, Kohat University of Science & Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan.
Department of Medical Lab Technology, Kohat University of Science & Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan.
BMC Neurol. 2023 Oct 4;23(1):353. doi: 10.1186/s12883-023-03397-y.
Intellectual disability (ID) is a condition that varies widely in both its clinical presentation and its genetic underpinnings. It significantly impacts patients' learning capacities and lowers their IQ below 70. The solute carrier (SLC) family is the most abundant class of transmembrane transporters and is responsible for the translocation of various substances across cell membranes, including nutrients, ions, metabolites, and medicines. The SLC13A3 gene encodes a plasma membrane-localized Na+/dicarboxylate cotransporter 3 (NaDC3) primarily expressed in the kidney, astrocytes, and the choroid plexus. In addition to three Na + ions, it brings four to six carbon dicarboxylates into the cytosol. Recently, it was discovered that patients with acute reversible leukoencephalopathy and a-ketoglutarate accumulation (ARLIAK) carry pathogenic mutations in the SLC13A3 gene, and the X-linked neurodevelopmental condition Christianson Syndrome is caused by mutations in the SLC9A6 gene, which encodes the recycling endosomal alkali cation/proton exchanger NHE6, also called sodium-hydrogen exchanger-6. As a result, there are severe impairments in the patient's mental capacity, physical skills, and adaptive behavior.
Two Pakistani families (A and B) with autosomal recessive and X-linked intellectual disorders were clinically evaluated, and two novel disease-causing variants in the SLC13A3 gene (NM 022829.5) and the SLC9A6 gene (NM 001042537.2) were identified using whole exome sequencing. Family-A segregated a novel homozygous missense variant (c.1478 C > T; p. Pro493Leu) in the exon-11 of the SLC13A3 gene. At the same time, family-B segregated a novel missense variant (c.1342G > A; p.Gly448Arg) in the exon-10 of the SLC9A6 gene. By integrating computational approaches, our findings provided insights into the molecular mechanisms underlying the development of ID in individuals with SLC13A3 and SLC9A6 mutations.
We have utilized in-silico tools in the current study to examine the deleterious effects of the identified variants, which carry the potential to understand the genotype-phenotype relationships in neurodevelopmental disorders.
智力障碍（ID）是一种临床表现和遗传基础差异很大的疾病。它显著影响患者的学习能力，并使他们的智商降低到 70 以下。溶质载体（SLC）家族是跨膜转运蛋白中最丰富的一类，负责将各种物质跨细胞膜转运，包括营养物质、离子、代谢物和药物。SLC13A3 基因编码一种位于质膜上的 Na+/二羧酸共转运蛋白 3（NaDC3），主要在肾脏、星形胶质细胞和脉络丛中表达。除了三个钠离子外，它还将四到六个碳二羧酸带入细胞质。最近发现，急性可逆性脑白质病伴 α-酮戊二酸堆积（ARLIAK）患者的 SLC13A3 基因存在致病性突变，X 连锁神经发育疾病 Christianson 综合征是由 SLC9A6 基因突变引起的，该基因编码再循环内体碱阳离子/质子交换体 NHE6，也称为钠-氢交换体-6。因此，患者的智力、身体技能和适应行为严重受损。
对两个巴基斯坦家族（A 和 B）进行了常染色体隐性和 X 连锁智力障碍的临床评估，并通过全外显子组测序鉴定了 SLC13A3 基因（NM 022829.5）和 SLC9A6 基因（NM 001042537.2）中的两个新的致病变异。家族 A 分离出 SLC13A3 基因外显子 11 中的一个新的纯合错义变异（c.1478C>T;p.Pro493Leu）。同时，家族 B 分离出 SLC9A6 基因外显子 10 中的一个新的错义变异（c.1342G>A;p.Gly448Arg）。通过整合计算方法，我们的发现为 SLC13A3 和 SLC9A6 突变个体 ID 发育的分子机制提供了见解。
我们在本研究中利用了计算工具来研究已识别变异的有害影响，这有可能帮助我们理解神经发育障碍中的基因型-表型关系。
