Structural and functional implications of SLC13A3 and SLC9A6 mutations: an in silico approach to understanding intellectual disability

BMC Neurology

Research

Adil U Rehman¹  Rooh Niaz¹  Syeda Iqra Hussain¹  Saadullah Khan¹  Sher Alam Khan¹  Niamatullah Khan¹  Noor Muhammad¹  Salah Ud Din Shah¹  Nazif Muhammad¹  Niamat Khan¹  Shoukat Ali Wasan²  Muhammad Usman Mirza³  Fardous Fardous⁴  Mehwish Siddique⁵  Hafiz Ullah⁶  Naveed Wasif⁷ 

[1]Department of Biotechnology and Genetic Engineering, Kohat University of Science & Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan

[2]Department of Botany, Faculty of Natural Sciences, Shah Abdul Latif University, Khairpur, Sindh, Pakistan

[3]Department of Chemistry and Biochemistry, University of Windsor, N9B 1C4, Windsor, ON, Canada

[4]Department of Medical Lab Technology, Kohat University of Science & Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan

[5]Department of Zoology, Government Post Graduate College for Women, Satellite Town, Gujranwala, Pakistan

[6]Gomal Center of Biochemistry and Biotechnology (GCBB), Gomal University D. I. Khan, D. I. Khan, Pakistan

[7]Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany

[8]Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

关键词: Intellectual disability;    Acute reversible leukoencephalopathy;    Christianson Syndrome;    Exome sequencing;    SLC13A3;    SLC9A6;    Molecular dynamics simulation;   

DOI  :  10.1186/s12883-023-03397-y

 received in 2023-05-24, accepted in 2023-09-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundIntellectual 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.Methods and resultsTwo 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.ConclusionWe 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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

【 图 表 】

Fig. 2

Fig. 1

Fig. 3

Fig. 8