Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A16
Cytogenetic location: 10q21.3 Genomic coordinates (GRCh38): 10:68,477,998-68,527,523 (from NCBI)
By screening a human thyroid expression library with antibody-rich sera from patients with Graves disease (275000), Zarrilli et al. (1989) isolated a cDNA clone, which they termed hGT, that was reactive with most of the sera. The predicted amino acid sequence of 348 residues exhibited strong homology with mitochondrial ADP/ATP carrier proteins (ADP/ATP translocators; see 103220, 300150, and 300151).
By somatic cell hybrid analysis, Zarrilli et al. (1989) mapped the Graves disease autoantigen to chromosome 10. Using the cDNA isolated by Zarrilli et al. (1989) as a probe, Rossi et al. (1993) further localized the GDA gene to 10q21.3-q22.1 by nonisotopic in situ hybridization.
Mitochondrial carrier proteins, which are localized in the inner membrane, facilitate the rapid transport and exchange of molecules between the cytosol and the mitochondrial matrix space. SLC25A16 is 35% identical to the yeast mitochondrial carrier protein Leu5. In yeast strains lacking Leu5, Prohl et al. (2001) detected reduced mitochondrial, but not cytosolic, CoA levels. Organelles from Leu5-negative cells were not capable of synthesis of alpha-isopropylmalate (IPM) because the IPM synthase was trapped in the mitochondria. Mutant yeast also lacked peroxisomal citrate synthase. Transformation of mutant yeast cells with a plasmid carrying SLC25A16 at least partially replaced Leu5 function, suggesting a role for SLC25A16 in mitochondrial function.
Associations Pending Confirmation
For discussion of a possible association between fingernail dysplasia and variation in the SLC25A16 gene, see 139080.0001.
This variant is classified as a variant of unknown significance because its contribution to fingernail dystrophy has not been confirmed.
Khan et al. (2018) studied a consanguineous Pakistani family segregating autosomal recessive fingernail dystrophy that showed linkage to a 22.34-Mb region on chromosome 10q11.23-q22.1, with a maximum 2-point lod score of 3.14 (theta = 0) and maximum multipoint lod score of 4.09. Whole-exome sequencing revealed homozygosity for a c.92G-T transversion in the SLC25A16 gene, resulting in an arg31-to-leu (R31L) substitution at a conserved residue, in the 5 affected sibs. Their unaffected parents and an unaffected sib were heterozygous for the mutation, which was present in the South Asian population of the ExAC database at a minor allele frequency of 0.00012. Functional analysis of the variant was not reported. Nail features were observed at birth in affected individuals, who ranged in age from 15 to 27 years and all exhibited a severe form of onychodystrophy. Digits had a bulbous appearance with mild erythema and swelling of the proximal and lateral nail folds. The nail bed was hyperkeratotic, and the nail plate was thickened and highly dystrophic; in some digits, the nail plate was completely destroyed. Disease severity varied among the affected individuals. Toenails were normal, and no defects were observed in other ectodermal structures.
Khan, S., Ansar, M., Khan, A. K., Shah, K., Muhammad, N., Shahzad, S., Nickerson, D. A., Bamshad, M. J., Santos-Cortez, R. L. P., Leal, S. M., Ahmad, W. A homozygous missense mutation in SLC25A16 associated with autosomal recessive isolated fingernail dysplasia in a Pakistani family. Brit. J. Derm. 178: 556-558, 2018. [PubMed: 28504827] [Full Text: https://doi.org/10.1111/bjd.15661]
Prohl, C., Pelzer, W., Diekert, K., Kmita, H., Bedekovics, T., Kispal, G., Lill, R. The yeast mitochondrial carrier Leu5p and its human homologue Graves' disease protein are required for accumulation of coenzyme A in the matrix. Molec. Cell Biol. 21: 1089-1097, 2001. [PubMed: 11158296] [Full Text: https://doi.org/10.1128/MCB.21.4.1089-1097.2001]
Rossi, E., Zarrilli, R., Zuffardi, O. Regional assignment of the gene coding for a human Graves' disease autoantigen to 10q21.3-q22.1. Hum. Genet. 90: 653-654, 1993. [PubMed: 8444471] [Full Text: https://doi.org/10.1007/BF00202485]
Zarrilli, R., Oates, E. L., McBride, O. W., Lerman, M. I., Chan, J. Y., Santisteban, P., Ursini, M. V., Notkins, A. L., Kohn, L. D. Sequence and chromosomal assignment of a novel cDNA identified by immunoscreening of a thyroid expression library: similarity to a family of mitochondrial solute carrier proteins. Molec. Endocr. 3: 1498-1508, 1989. [PubMed: 2575220] [Full Text: https://doi.org/10.1210/mend-3-9-1498]