ClinVar Genomic variation as it relates to human health

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. (less)

Abnormality of the amniotic fluid (present) , Premature birth (present) , Abnormality of the umbilical cord (present) , Hemihypertrophy (present) , Short stature (present) , Failure to thrive (present) , Abnormality of the chin (present) , Abnormal facial shape (present) , Abnormality of the hair (present) , Abnormality of the oral cavity (present) , Abnormality of the skull (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Ear malformation (present) , Conductive hearing impairment (present) , Hyperhidrosis (present) , Abnormality of limb bone morphology (present) , Abnormality of digit (present) , Abnormality of cardiovascular system morphology (present) , Feeding difficulties (present) , Abnormality of the urethra (present) , Abnormality of primary teeth (present) (less)