Alternative titles; symbolsMITOCHONDRIAL UNCOUPLING PROTEIN 1; MUP1MITOCHONDRIAL THIAMINE PYROPHOSPHATE CARRIER; TPCMITOCHONDRIAL DEOXYNUCLEOTIDE CARRIER, FORMER...
Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A19
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38): 17:75,272,979-75,289,957 (from NCBI)
The SLC25A19 gene encodes a mitochondrial thiamine pyrophosphate carrier (Lindhurst et al., 2006).
▼ Cloning and Expression
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).
▼ Gene Structure
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.
▼ Molecular Genetics
Rosenberg et al. (2002) found a homozygous mutation in the SLC25A19 gene (G177A: 606521.0001) to be the cause of Amish microcephaly (MCPHA; 607196).
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.
▼ Animal Model
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.
▼ ALLELIC VARIANTS ( 2 Selected Examples):
.0001 MICROCEPHALY, AMISH TYPE
Rosenberg et al. (2002) demonstrated that Amish lethal microcephaly (607196) is caused by homozygosity for a 530G-C transversion in the SLC25A19 gene, predicted to produce a gly177-to-ala (G177A) substitution in the first residue of the fourth transmembrane domain (Spiegel et al., 2009).
.0002 THIAMINE METABOLISM DYSFUNCTION SYNDROME 4 (BILATERAL STRIATAL DEGENERATION AND PROGRESSIVE POLYNEUROPATHY TYPE)
In 4 affected sibs, born of consanguineous Arab Muslim parents, with bilateral striatal necrosis and progressive polyneuropathy due to thiamine metabolism dysfunction (THMD4; 613710), Spiegel et al. (2009) identified a homozygous 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.