First Identification of Mutations in the Human SLC5A6 Gene Associated with Brain, Immune, Bone and Intestinal Dysfunction.

Nova Southeastern University, Davie, Florida, USA

Introduction. Biotin (vitamin B7) is indispensable for normal cellular metabolism due to involvement in many critical metabolic pathways including fatty acid, amino acid and energy metabolism; it also plays a role in regulating cellular level of reactive oxygen species and gene expression, as well as normal immune function/response. Human (mammalian) cells cannot synthesize biotin endogenously; they obtain the vitamin across the plasma membrane via a carrier-mediated uptake process - human sodium-dependent multivitamin transporter (hSMVT; encoded by SLC5A6 gene); this system also transports pantothenic acid and lipoate. Case presentation. Using whole exome sequencing (GeneDx), we describe the first identification of two mutations in SLC5A6 gene in a young child: R94X [(CGA>TGA) c280 C>T] and R123L [(CGC>CTC), c368 G>T]. Both mutations are located in exon 3 of SLC5A6 gene. The child exhibited failure to thrive, microcephaly, brain changes, cerebral palsy, developmental delay, immunodeficiency, severe gastro-esophageal reflux, osteoporosis and pathologic bone fractures. After identification of the hSMVT mutations, he responded favorably to supplemental administration of pharmacological doses of biotin, pantothenic acid and lipoate. Experimental characterization of the identified mutations utilizing human-derived intestinal HuTu-80 and brain U87 cell lines, showed impaired functionality (3H-biotin uptake) of the two identified hSMVT mutants. In addition, our results (using live-cell confocal imaging) showed poor expression and cytoplasmic localization of the R94X mutant, while the R123L mutant was predominantly retained in the endoplasmic reticulum. Conclusion. This is the first reporting of mutations in the human SLC5A6 gene leading to defects in hSMVT, associated with a host of clinical abnormalities.