title: Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child.
abstract: The human sodium-dependent multivitamin transporter (hSMVT) is a product of the SLC5A6 gene and mediates biotin, pantothenic acid, and lipoate uptake in a variety of cellular systems. We report here the identification of mutations R94X, a premature termination, and R123L, a dysfunctional amino acid change, both in exon 3 of the SLC5A6 gene in a child using whole genome-scanning. At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures. After identification of the SLC5A6 mutations, he responded clinically to supplemental administration of excess biotin, pantothenic acid, and lipoate with improvement in clinical findings. Functionality of the two mutants was examined by3H-biotin uptake assay following expression of the mutants in human-derived intestinal HuTu-80 and brain U87 cells. The results showed severe impairment in biotin uptake in cells expressing the mutants compared to those expressing wild-type hSMVT. Live cell confocal imaging of cells expressing the mutants showed the R94X mutant to be poorly tolerated and localized in the cytoplasm, while the R123L mutant was predominantly retained in the endoplasmic reticulum. This is the first reporting of mutations in the SLC5A6 gene in man, and suggests that this gene is important for brain development and a wide variety of clinical functions.
authors.affiliation: Departments of Medicine and Physiology/Biophysics, University of California, Irvine, CA 92697.|Department of Veterans Affairs Medical Center, Long Beach, CA 90822.
authors.forename: Veedamali S
authors.initials: VS
authors.lastname: Subramanian
authors.affiliation: Divisions of Nephrology, Joe DiMaggio Children's Hospital and the Charles E Schmidt College of Medicine, Hollywood, FL 33021.
authors.forename: Alexandru R
authors.initials: AR
authors.lastname: Constantinescu
authors.affiliation: Divisions of Genetics, Joe DiMaggio Children's Hospital and the Charles E Schmidt College of Medicine, Hollywood, FL 33021.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Benke
authors.affiliation: Departments of Medicine and Physiology/Biophysics, University of California, Irvine, CA 92697.|Department of Veterans Affairs Medical Center, Long Beach, CA 90822.
authors.forename: Hamid M
authors.initials: HM
authors.lastname: Said
mesh_terms: D001710:Biotin / Q000008:administration & dosage / Q000493:pharmacokinetics; D001847:Bone Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D001927:Brain Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D005091:Exons; D015894:Genome, Human; D006801:Humans; D007223:Infant; D007410:Intestinal Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009154:Mutation; D010205:Pantothenic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D027981:Symporters / Q000235:genetics*; D008063:Thioctic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D027981:Symporters; C119981:biotin transporter; D010205:Pantothenic Acid; D001710:Biotin; D008063:Thioctic Acid