First identification of mutations in the human SLC5A6 gene associated with brain, immune, bone and intestinal dysfunction
Bibliographic record
Abstract
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
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".