SLC25A24 – Fontaine progeroid syndrome

Fontaine progeroid syndrome (FPS) is an autosomal dominant disorder characterized by prenatal and postnatal growth retardation, lipoatrophy, cutis laxa with premature skin wrinkling, sparse hair, craniofacial dysmorphism including coronal craniosynostosis and wide anterior fontanel, digital hypoplasia, and umbilical hernia. Initially described under Gorlin-Chaudhry-Moss and Fontaine-Farriaux syndromes, FPS unifies these entities under a common genetic basis in SLC25A24, encoding the mitochondrial ATP-Mg/Pi carrier SCaMC-1. Clinical diagnosis is supported by identification of heterozygous de novo SLC25A24 missense variants altering Arg217.

Genetic studies have identified recurrent de novo variants at codon 217: c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys). In a cohort of five unrelated females with Gorlin-Chaudhry-Moss syndrome, exome and genome sequencing revealed these variants in all affected individuals ([PMID:29100093]). Three additional unrelated cases—a 15-year-old male with p.Arg217His ([PMID:30329211]), a Korean girl with the same p.Arg217His ([PMID:31775791]), and an infant fatal case ([PMID:36093452])—confirm eight unrelated probands harboring de novo pathogenic SLC25A24 variants, with no transmitted familial cases noted.

Variant spectrum is narrow, comprising exclusively missense changes at Arg217. Both p.Arg217His and p.Arg217Cys have been observed recurrently across all reported FPS cases, suggesting a mutational hotspot and supporting a gain-of-function mechanism rather than loss-of-function or haploinsufficiency.

Functional assays demonstrate that Arg217 substitutions induce mitochondrial dysfunction. Patient fibroblasts and cells overexpressing mutant SCaMC-1 show marked mitochondrial swelling, elevated membrane potential upon H2O2 exposure, and reduced matrix ATP content under basal conditions ([PMID:29100093]). Molecular dynamics simulations predict a narrowed substrate cavity and disrupted transporter dynamics secondary to Arg217 substitutions ([PMID:29100094]). These findings confirm a gain of pathological function leading to impaired energy homeostasis in skeletal and connective tissues.

No conflicting evidence disputing SLC25A24’s role in FPS has been reported. The consistent phenotype across multiple case reports and functional studies reinforces the association and excludes alternative genetic etiologies.

In summary, heterozygous de novo missense variants at Arg217 in SLC25A24 cause autosomal dominant Fontaine progeroid syndrome through a gain-of-function mechanism that disrupts mitochondrial ATP-Mg/Pi transport. Genetic testing for Arg217 substitutions in SLC25A24 should be considered in patients presenting with progeroid features, craniosynostosis, lipoatrophy, and characteristic dysmorphism, enabling precise diagnosis, management, and genetic counseling.

References

• American journal of human genetics • 2017 • De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction. PMID:29100093
• American journal of human genetics • 2017 • De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise. PMID:29100094
• American journal of medical genetics. Part A • 2018 • A rare male patient with Fontaine progeroid syndrome caused by p.R217H de novo mutation in SLC25A24. PMID:30329211
• BMC medical genetics • 2019 • A 9-year-old Korean girl with Fontaine progeroid syndrome: a case report with further phenotypical delineation and description of clinical course during long-term follow-up. PMID:31775791
• Clinical case reports • 2022 • Fontaine progeroid syndrome-A case report. PMID:36093452

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