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First identification of mutations in the human SLC5A6 gene associated with brain, immune, bone and intestinal dysfunction
Author(s) -
Subramanian Veedamali,
Benke Paul,
Constantinescu Alexandru,
Said Hamid
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1008.4
Subject(s) - biology , mutation , microbiology and biotechnology , biochemistry , gene
Biotin (vitamin B7) is indispensable for normal cellular metabolism due to its involvement in a variety of 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; rather they obtain the vitamin across the plasma membrane via a carrier‐mediated uptake process that involves the human sodium‐dependent multivitamin transporter (hSMVT; product of the SLC5A6 gene); this system also transports pantothenic acid and lipoate. We report here, using whole exome sequencing (GeneDx), the first identification of two mutations in the SLC5A6 gene in a young child: R94X [(CGA>TGA) c280 C>T] and R123L [(CGC>CTC), c368 G>T]. Both of these mutations are located in exon 3 of the SLC5A6 gene. The child exhibited many clinical manifestations including 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, the child 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. This is the first reporting of mutations in the human SLC5A6 gene that lead to defects in hSMVT function and cell biology, and is associated with a host of clinical abnormalities. Support or Funding Information Supported by a grant from the DVA, by NIH grants DK58057, DK56057, DK10747, and the Gordon Foundation