Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A19
SNOMEDCT: 702437000, 771305006;
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38) : 17:75,272,992-75,289,433 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.1 | Microcephaly, Amish type | 607196 | Autosomal recessive | 3 |
| Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type) | 613710 | Autosomal recessive | 3 |
The SLC25A19 gene encodes a mitochondrial thiamine pyrophosphate carrier (Lindhurst et al., 2006).
The inner membranes of mitochondria contain a family of proteins that transport various substances, including deoxynucleotides, into and out of the matrix. By phylogenetic analysis and EST database searching for mitochondrial carrier protein and adenine nucleotide carrier (ANC; see 103220)-like sequences, Dolce et al. (2001) obtained a cDNA encoding SLC25A19, which they termed DNC. The deduced 320-amino acid, 6-transmembrane DNC protein, which is 22% identical to mammalian ANCs, contains a P box, which is found in the DNA-binding domain of nuclear receptors. SDS-PAGE analysis showed that the purified recombinant protein has an apparent molecular mass of 36 kD. Functional analysis showed that DNC catalyzes the transport of all 4 deoxynucleotide diphosphates (dNDPs) and, less efficiently, the corresponding dNTPs in exchange for dNDPs, ADP, or ATP. It did not transport dNMPs, NMPs, deoxynucleosides, nucleosides, purines, or pyrimidines. RT-PCR analysis revealed expression of DNC in all tissues tested except placenta, with highest levels in colon, kidney, lung, testis, spleen, and brain. Immunoblot analysis detected expression in rat kidney, liver, and lung mitochondria. Dolce et al. (2001) proposed that the greater efficiency of DNC in the exchange of dideoxy NTPs suggests that ddNDPs may be the best substrate transported by DNC and that DNC may be involved directly in the cytotoxicity of antiviral and anticancer nucleoside analogs.
Lindhurst et al. (2006) reported that Slc25a19 is a carrier of mitochondrial thiamine pyrophosphate (TPC).
By PCR and genomic sequence analysis, Iacobazzi et al. (2001) determined that the SLC25A19 gene contains 9 exons and spans 16.5 kb. RT-PCR analysis suggested the existence of splice variants at the 5-prime end.
Using FISH, Iacobazzi et al. (2001) mapped the SLC25A19 gene to 17q25.3.
Microcephaly, Amish Type
Rosenberg et al. (2002) found a homozygous mutation in the SLC25A19 gene (G177A: 606521.0001) to be the cause of Amish-type microcephaly (MCPHA; 607196), also known as thiamine metabolism dysfunction syndrome-3 (THMD3).
Thiamine Metabolism Dysfunction Syndrome 4
By homozygosity mapping followed by candidate gene analysis of a consanguineous Arab Muslim family with bilateral striatal necrosis and progressive polyneuropathy due to thiamine metabolism dysfunction (THMD4; 613710), Spiegel et al. (2009) identified a homozygous mutation in the SLC25A19 gene (G125S; 606521.0002). Spiegel et al. (2009) noted that the phenotype was less severe than that described in Amish lethal microcephaly, and suggested that the G125S mutation was less deleterious than the G177A mutation.
In an Italian patient, born to consanguineous parents, with THMD4, Bottega et al. (2019) identified a homozygous mutation in the SLC25A19 gene (Q192H; 606521.0003). SLC25A19 with the Q192H mutation in HepG2 cells showed reduced expression in mitochondrial and whole cell homogenates compared to wildtype. The patient had clinical features of episodic encephalopathy and progressive axonal polyneuropathy.
In 2 unrelated Indian children, born to consanguineous parents, with THMD4, Gowda et al. (2019) identified homozygous missense mutations in the SLC25A19 gene (E304K, 606521.0004; L290Q, 606521.0005). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were identified in heterozygous state in both sets of parents. Functional studies were not performed. Both patients presented with recurrent episodes of flaccid paralysis and encephalopathy following febrile illness.
Li et al. (2020) identified compound heterozygous mutations in the SLC25A19 gene in 2 patients with THMD4: A65V and P152T (patient 5) and A161T and A184P (patient 6). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were identified in the carrier state in the parents. Functional studies were not performed. Both patients had recurrent encephalopathic episodes, abnormal signal in the putamen and caudate nucleus on brain MRI, and elevated alpha-ketoglutarate in the urine.
Chen et al. (2021) identified compound heterozygous mutations in the SLC25A19 gene in 2 Chinese sibs (G26R, 606521.0006 and F249I, 606521.0007) and an unrelated Chinese child (A57T and A128V) with THMD4. Transfection of each mutation into HEK293 cells resulted in decreased mitochondrial thiamine pyrophosphate (TPP) compared to wildtype, indicative of deficient TPP transport. All 3 patients presented with basal ganglia changes on brain MRI following fever.
In 2 Turkish sibs and an unrelated Turkish patient with THMD4, Samur et al. (2022) identified homozygosity for a previously reported missense mutation in the SLC25A19 gene (Q192H; 606521.0003). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing.
Lindhurst et al. (2006) found that Slc25a19-knockout mice had 100% prenatal lethality by embryonic day 12. Affected embryos had neural tube closure defects with ruffling of the neural fold ridges, yolk sac erythropoietic failure, and increased alpha-ketoglutarate in the amniotic fluid. Mitochondria from these animals showed normal levels of RNA and DNA, suggesting that transport of these molecules is not a primary role of Slc25a19. In contrast, mitochondria from these animals and from cells of patients with MCPHA had undetectable and decreased thiamine pyrophosphate levels, respectively, resulting in dysfunction of the alpha-ketoglutarate dehydrogenase complex (see 126063). The findings indicated that transport of this molecule is a candidate function of Slc25a19.
Rosenberg et al. (2002) demonstrated that Amish-type microcephaly (MCPHA; 607196), also known as thiamine metabolism dysfunction syndrome-3 (THMD3), is caused by homozygosity for a c.530G-C transversion in the SLC25A19 gene, predicted to result in a gly177-to-ala (G177A) substitution in the first residue of the fourth transmembrane domain (Spiegel et al., 2009).
In 4 affected sibs, born of consanguineous Arab Muslim parents, with bilateral striatal necrosis and progressive polyneuropathy due to thiamine metabolism dysfunction-4 (THMD4; 613710), Spiegel et al. (2009) identified a homozygous c.373G-A transition in the SLC25A19 gene, resulting in a gly125-to-ser (G125S) substitution in the highly conserved first residue of the third transmembrane domain. Functional complementation studies in yeast showed decreased protein function compared to controls. The phenotype was characterized by recurrent encephalopathic episodes in childhood with essentially full psychomotor recovery, as well as by a chronic progressive polyneuropathy. Cognition was intact. Spiegel et al. (2009) noted that the phenotype was much less severe than that described in Amish lethal microcephaly (607196), and suggested that the G125S mutation was less deleterious than the G177A mutation.
In an Italian patient, born to consanguineous parents, with thiamine metabolism dysfunction syndrome-4 (THMD4; 613710), Bottega et al. (2019) identified a homozygous c.576G-C transversion at a conserved site in exon 6 of the SLC25A19 gene, resulting in a gln192-to-his (Q192H) substitution. The mutation, which was identified by a combination of homozygosity mapping and sequencing of the SLC25A19 gene, was present in heterozygous state in the parents. The mutation was not present in the ExAC, 1000 Genomes Project, and gnomAD databases. Expression of SLC25A19 with the Q192H mutation into HepG2 cells showed reduced protein expression in mitochondrial and whole cell homogenates compared to wildtype.
In 2 Turkish brothers and an unrelated Turkish female with THMD4, Samur et al. (2022) identified homozygosity for the Q192H mutation in the SLC25A19 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the families. Functional studies were not performed.
In an Indian boy, born to consanguineous parents, with thiamine metabolism dysfunction syndrome-4 (THMD4; 613710), Gowda et al. (2019) identified a homozygous c.910G-A transition in the SLC25A19 gene, resulting in a glu304-to-lys (E304K) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was identified in heterozygous state in the parents. Functional studies were not performed.
In an Indian girl, born to consanguineous parents, with thiamine metabolism dysfunction syndrome-4 (THMD4; 613710), Gowda et al. (2019) identified a homozygous c.869T-A transversion in the SLC25A19 gene, resulting in a leu290-to-gln (L290Q) substitution. The mutation, which was identified with next generation sequencing and confirmed with Sanger sequencing, was found in the heterozygous state in both parents. Functional studies were not performed.
In 2 Chinese sibs (patients 2 and 3) with thiamine metabolism dysfunction syndrome-4 (THMD4; 613710), Chen et al. (2021) identified compound heterozygous mutations in the SLC25A19 gene: a c.76G-A transition (c.76G-A, NM_001126122), resulting in a gly26-to-arg (G26R) substitution, and a c.745T-A transversion, resulting in a phe249-to-ile (F249I; 606521.0007) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were present in heterozygous state in the parents. The G26R mutation was present in the gnomAD database at a frequency of 0.0005 in the East Asian population. The F249I mutation was not present in the gnomAD database in the East Asian population. Transfection of each mutation into HEK293 cells resulted in deficient mitochondrial transport of thiamine pyrophosphate compared to wildtype.
For discussion of the c.745T-A transversion (c.745T-A, NM_001126122) in the SLC25A19 gene, resulting in a phe249-to-ile (F249I) substitution, that was identified in compound heterozygous state in 2 Chinese sibs with thiamine metabolism dysfunction syndrome-4 (THMD4; 613710) by Chen et al. (2021), see 606521.0006.
Bottega, R., Perrone, M. D., Vecchiato, K., Taddio, A., Sabui, S., Pecile, V., Said, H. M., Faletra, F. Functional analysis of the third identified SLC25A19 mutation causative for the thiamine metabolism dysfunction syndrome 4. J. Hum. Genet. 64: 1075-1081, 2019. [PubMed: 31506564] [Full Text: https://doi.org/10.1038/s10038-019-0666-5]
Chen, Y., Fang, B., Hu, X., Guo, R., Guo, J., Fang, K., Ni, J., Li, W., Qian, S., Hao, C. Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4. Orphanet J. Rare Dis. 16: 403, 2021. [PubMed: 34587972] [Full Text: https://doi.org/10.1186/s13023-021-02028-4]
Dolce, V., Fiermonte, G., Runswick, M. J., Palmieri, F., Walker, J. E. The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals. Proc. Nat. Acad. Sci. 98: 2284-2288, 2001. [PubMed: 11226231] [Full Text: https://doi.org/10.1073/pnas.031430998]
Gowda, V. K., Srinivasan, V. M., Jehta, K., Bhat, M. D. Bilateral striatal necrosis with polyneuropathy with a novel SLC25A19 (mitochondrial thiamine pyrophosphate carrier OMIM*606521) mutation: treatable thiamine metabolic disorder--a report of two Indian cases. Neuropediatrics 50: 313-317, 2019. [PubMed: 31295743] [Full Text: https://doi.org/10.1055/s-0039-1693148]
Iacobazzi, V., Ventura, M., Fiermonte, G., Prezioso, G., Rocchi, M., Palmieri, F. Genomic organization and mapping of the gene (SLC25A19) encoding the human mitochondrial deoxynucleotide carrier (DNC). Cytogenet. Cell Genet. 93: 40-42, 2001. [PubMed: 11474176] [Full Text: https://doi.org/10.1159/000056945]
Li, D., Song, J., Li, X., Liu, Y., Dong, H., Kang, L., Liu, Y., Zhang, Y., Jin, Y., Guan, H., Zhou, C., Yang, Y. Eleven novel mutations and clinical characteristics in seven Chinese patients with thiamine metabolism dysfunction syndrome. Europ. J. Med. Genet. 63: 104003, 2020. [PubMed: 32679198] [Full Text: https://doi.org/10.1016/j.ejmg.2020.104003]
Lindhurst, M. J., Fiermonte, G., Song, S., Struys, E., De Leonardis, F., Schwarzberg, P. L., Chen, A., Castegna, A., Verhoeven, N., Mathews, C. K., Palmieri, F., Biesecker, L. G. Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. Proc. Nat. Acad. Sci. 103: 15927-15932, 2006. [PubMed: 17035501] [Full Text: https://doi.org/10.1073/pnas.0607661103]
Rosenberg, M. J., Agarwala, R., Bouffard, G., Davis, J., Fiermonte, G., Hilliard, M. S., Koch, T., Kalikin, L. M., Makalowska, I., Morton, D. H., Petty, E. M., Weber, J. L., Palmieri, F., Kelley, R. I., Schaffer, A. A., Biesecker, L. G. Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nature Genet. 32: 175-179, 2002. [PubMed: 12185364] [Full Text: https://doi.org/10.1038/ng948]
Samur, B. M., Gumus, G., Canpolat, M., Gumus, H., Per, H., Caglayan, A. O. Clinical and genetic studies of thiamine metabolism dysfunction syndrome-4: case series and review of the literature. Clin. Dysmorph. 31: 125-131, 2022. [PubMed: 35102031] [Full Text: https://doi.org/10.1097/MCD.0000000000000411]
Spiegel, R., Shaag, A., Edvardson, S., Mandel, H., Stepensky, P., Shalev, S. A., Horovitz, Y., Pines, O., Elpeleg, O. SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis. Ann. Neurol. 66: 419-424, 2009. [PubMed: 19798730] [Full Text: https://doi.org/10.1002/ana.21752]