Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A24
SNOMEDCT: 770567006;
Cytogenetic location: 1p13.3 Genomic coordinates (GRCh38) : 1:108,134,043-108,200,343 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.3 | Fontaine progeroid syndrome | 612289 | Autosomal dominant | 3 |
By searching an EST database using the rabbit peroxisomal carrier Efinal as query, followed by PCR of a heart cDNA library and RT-PCR of HEK293 cell total RNA, del Arco and Satrustegui (2004) cloned SLC25A24, which they designated SCAMC1. The deduced 477-amino acid protein contains an N-terminal calcium-binding domain, followed by 6 transmembrane regions and a short C terminus. The calcium-binding domain shares 25% identity with calmodulin (see 114180), with 4 EF-hand motifs at conserved positions. SCAMC1 also shares significant similarity with SCAMC2 (SLC25A25; 608745) and SCAMC3 (SLC25A23; 608746), with most differences in the N termini and EF-hand 1. Northern blot analysis detected a 3.4-kb SCAMC1 transcript in all tissues examined, and expression of SCAMC1 was generally higher than that of SCAMC2 or SCAMC3. Both endogenous and transfected epitope-tagged SCAMC1 were expressed in a subcellular pattern that overlapped with a mitochondrial marker. Western blot analysis of mitochondria-enriched fractions of a number of cell lines showed that SCAMC1 migrated at an apparent molecular mass of 48 to 50 kD.
Del Arco and Satrustegui (2004) determined that the SLC25A24 gene contains 10 exons and spans about 65 kb. The mouse Slc25a24 gene has an identical genomic organization.
By genomic sequence analysis, del Arco and Satrustegui (2004) mapped the SLC25A24 gene to chromosome 1p36.13. They mapped the mouse Slc25a24 gene to a region of chromosome 2B that shows homology of synteny to human chromosome 1p36.13.
In 5 unrelated girls with Fontaine progeroid syndrome (FPS; 612289), 1 of whom died at age 20 months, Ehmke et al. (2017) identified heterozygosity for 2 different de novo missense mutations in the SLC25A24 gene, both occurring at the same codon: R217H (608744.0001) in 4 patients, and R217C (608744.0002) in 1 patient.
In 4 unrelated patients with FPS, who all died within the first year of life, Writzl et al. (2017) identified heterozygosity for the same 2 de novo missense mutations in the SLC25A24 gene at the R217 codon that had previously been reported by Ehmke et al. (2017): 3 of the patients carried the R217H variant, and 1 had the R217C variant. Functional analysis demonstrated that the mutations clearly affect mitochondrial morphology, and also suggested an impact on oxidative phosphorylation via decreased ATP synthesis and an increase in the mitochondrial membrane potential, thus creating conditions that are inhospitable to cell proliferation.
In 4 unrelated girls with Fontaine progeroid syndrome (FPS; 612289), including a Hungarian girl originally reported by Adolphs et al. (2011), Ehmke et al. (2017) identified heterozygosity for a de novo c.650G-A transition (c.650G-A, NM_013386.4) in exon 5 of the SLC25A24 gene, resulting in an arg217-to-his (R217H) substitution at a highly conserved residue in the predicted helix 1 of the transmembrane domain. The mutation was not found in the ExAC, gnomAD, or 1000 Genomes Project databases. Skin fibroblasts from 2 of the patients (patients 1 and 4) showed mitochondrial swelling, which developed into ballooning after induction of oxidative stress by treatment with H2O2, whereas control fibroblasts appeared almost unchanged; these findings were corroborated by transmission electron microscopy. In transfected HeLa cells, wildtype and mutant proteins both localized to mitochondria, but there was mitochondrial swelling and increased fragmentation with the mutant, which was more pronounced after treatment with H2O2. The mitochondrial membrane potential (MMP) showed no abnormality in patient fibroblasts under normal conditions; however, after treatment with H2O2, the MMP appeared higher in mutant fibroblasts than in control cells, indicating an altered proton gradient. Analysis of the ATP content of the mitochondrial matrix using firefly luciferase, an ATP-dependent enzyme, showed that patient fibroblasts had reduced firefly activity, consistent with a reduced matrix ATP content. Three of the patients were alive at ages 5, 5.5, and 7 years at last exam, but 1 patient (patient 4), a Turkish girl, died at age 20 months from a urinary tract infection.
In 3 unrelated infants with FPS, including a Slovenian male infant (patient 1), a French female infant (patient 2) originally reported by Faivre et al. (1999), and an Italian male newborn (patient 4) previously described by Castori et al. (2009), Writzl et al. (2017) identified heterozygosity for the R217H mutation in SLC25A24, at a residue located just below the m-gate of the carrier, within the fully conserved mitochondrial carrier family (MCF) signature. The mutation was not found in the Slovenian exome database or the dbSNP (build 141), gnomAD, GoNL, or UK10K databases. Patient fibroblasts showed localization of the mutant protein to mitochondria, which were enlarged and swollen close to the nucleus; electron microscopy revealed abnormal cristae, which were larger and more dense in the swollen mitochondria than in normal mitochondria. Overexpression of the R217H mutant in HeLa and COS-7 cells showed abnormal swollen mitochondria similar to those observed in patient fibroblasts; however, in contrast to patient fibroblasts, the entire mitochondrial network appeared homogeneously affected. The Italian male newborn died at 20 hours of life from respiratory distress, and the other 2 patients died at 6 months and 7 months of age, from pulmonary hypertension and sepsis, respectively.
In a 14-year-old girl of northern European ancestry (patient 5) with Fontaine progeroid syndrome (FPS; 612289), Ehmke et al. (2017) identified heterozygosity for a de novo c.649C-T transition (c.649C-T, NM_013386.4) in exon 5 of the SLC25A24 gene, resulting in an arg217-to-cys (R217C) substitution at a highly conserved residue in the predicted helix 1 of the transmembrane domain. The mutation was not found in the ExAC, gnomAD, or 1000 Genomes Project databases.
In a Spanish female newborn (patient 3) with FPS, who was originally described by Rodriguez et al. (1999) and who died at 7 hours of life from respiratory distress, Writzl et al. (2017) identified heterozygosity for the R217C mutation in SLC25A24, at a residue located just below the m-gate of the carrier, within the fully conserved MCF signature. The mutation was not found in the Slovenian exome database or the dbSNP (build 141), gnomAD, GoNL, or UK10K databases. Overexpression of the R217C mutant in HeLa and COS-7 cells showed abnormal swollen mitochondria. HeLa cells expressing the R217C mutant showed lower protein levels than wildtype cells, and were obtained at lower frequency, suggesting a detrimental effect of R217C on cellular viability. This was confirmed using the xCELLigence biosensor system, which showed that the cell index was lower in mutant HeLa cells than wildtype, and that mutant cells exhibited a lower cell proliferation rate than controls. In addition, the basal mitochondrial membrane potential was higher in R217C-expressing HeLa cell lines and in patient fibroblasts than in control cells, and the contribution of ATP synthesis to basal mitochondrial respiration was clearly lower with the R217C mutant than with wildtype, indicating that mitochondrial hyperpolarization is associated with impaired ATP synthesis by mutant mitochondria. Analysis of mitochondrial ATP after inhibition by oligomycin was consistent with increased ATP demand in mutant cells, suggesting that the primary effect of the R217C mutation is not decreased ATP demand but decreased mitochondrial ATP production, which increases the membrane potential, with a subsequent increase in proton leak.
Adolphs, N., Klein, M., Haberl, E. J., Graul-Neumann, L., Menneking, H., Hoffmeister, B. Necrotizing soft tissue infection of the scalp after fronto-facial advancement by internal distraction in a 7-year-old girl with Gorlin-Chaudhry-Moss syndrome--a case report. J. Craniomaxillofac. Surg. 39: 554-561, 2011. [PubMed: 21216154] [Full Text: https://doi.org/10.1016/j.jcms.2010.11.016]
Castori, M., Silvestri, E., Pedace, L., Marseglia, G., Tempera, A., Antigoni, I., Torricelli, F., Majore, S., Grammatico, P. Fontaine-Farriaux syndrome: a recognizable craniosynostosis syndrome with nail, skeletal, abdominal, and central nervous system anomalies. Am. J. Med. Genet. 149A: 2193-2199, 2009. [PubMed: 19731360] [Full Text: https://doi.org/10.1002/ajmg.a.32763]
del Arco, A., Satrustegui, J. Identification of a novel human subfamily of mitochondrial carriers with calcium-binding domains. J. Biol. Chem. 279: 24701-24713, 2004. [PubMed: 15054102] [Full Text: https://doi.org/10.1074/jbc.M401417200]
Ehmke, N., Graul-Neumann, L., Smorag, L., Koenig, R., Segebrecht, L., Magoulas, P., Scaglia, F., Kilic, E., Hennig, A. F., Adolphs, N., Saha, N., Fauler, B., and 20 others. De novo mutations in SLC25A24 cause a craniosynostosis syndrome with hypertrichosis, progeroid appearance, and mitochondrial dysfunction. Am. J. Hum. Genet. 101: 833-843, 2017. [PubMed: 29100093] [Full Text: https://doi.org/10.1016/j.ajhg.2017.09.016]
Faivre, L., Khau Van Kien, P., Madinier-Chappat, N., Nivelon-Chevallier, A., Beer, F., LeMerrer, M. Can Hutchinson-Gilford progeria syndrome be a neonatal condition? (Letter) Am. J. Med. Genet. 87: 450-452, 1999. [PubMed: 10594888] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19991222)87:5<450::aid-ajmg16>3.0.co;2-t]
Rodriguez, J. I., Perez-Alonso, P., Funes, R., Perez-Rodriguez, J. Lethal neonatal Hutchinson-Gilford progeria syndrome. Am. J. Med. Genet. 82: 242-248, 1999. [PubMed: 10215548]
Writzl, K., Maver, A., Kovacic, L. Martinez-Valero, P., Contreras, L., Satrustegui, J., Castori, M., Faivre, L., Lapunzina, P., van Kuilenburg, A. B. P., Radovic, S., Thauvin-Robinet, C., Peterlin, B., del Arco, A., Hennekam, R. C. De novo mutations in SLC25A24 cause a disorder characterized by early aging, bone dysplasia, characteristic face, and early demise. Am. J. Hum Genet. 101: 844-855, 2017. [PubMed: 29100094] [Full Text: https://doi.org/10.1016/j.ajhg.2017.09.017]