Progeroid malformation syndrome caused by SLC25A24 mutations
An international group of researchers have revealed de novo mutations in SLC25A24 as the genetic cause of Gorlin-Chaudry-Moss syndrome (GCMS) in five affected children. This congenital disease manifests as a combination of malformations of the head and face, short stature, hair anomalies, small eyes, and shortened fingers/toes. Reduced subcutaneous fat and loose skin give some patients a progeroid appearance. To date, only a few affected individuals have been described worldwide. Researchers at the Institute of Human Genetics Göttingen have contributed to the elucidation of the genetic cause of this extremely rare disease: Using exome sequencing, they uncovered a disease-associated variant of SLC25A24 in their patient, a girl who had initially been diagnosed with a suspected neonatal progeroid syndrome. Their work has been funded by SFB1002.
SLC25A24 encodes a protein of the mitochondrial inner membrane. Interestingly, the identified mutations in all five children of the study affect the same amino acid of the SLC25A24 protein, which suggests a specific pathogenic mechanism. Functional investigations performed by the researchers in this study showed that the mutations cause mitochondrial dysfunction and that mutated cells are more susceptible to oxidative stress in vitro. The results, which have now been published in the American Journal of Human Genetics, suggest that the signs of premature aging in the patients are due to a disturbed development of skeletal, fat and connective tissue caused by dysfunction of the mitochondrial membrane transporter.
De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.
Ehmke N, Graul-Neumann L, Smorag L, Koenig R, Segebrecht L, Magoulas P, Scaglia F, Kilic E, Hennig AF, Adolphs N, Saha N, Fauler B, Kalscheuer VM, Hennig F, Altmüller J, Netzer C, Thiele H, Nürnberg P, Yigit G, Jäger M, Hecht J, Krüger U, Mielke T, Krawitz PM, Horn D, Schuelke M, Mundlos S, Bacino CA, Bonnen PE, Wollnik B, Fischer-Zirnsak B, Kornak U.
Am J Hum Genet. 2017 Nov 2;101(5):833-843. doi: 10.1016/j.ajhg.2017.09.016.
Progeroid syndromes are a key research area of the Wollnik Group at the Institute of Human Genetics. The Institute also runs a specialized Center for Progeroid Syndromes together with the Children’s Hospital as part of the Center of Rare Diseases Göttingen (ZSEG). It unites research and diagnostics related to this rare group of diseases and provides interdisciplinary care to patients with progeroid syndromes.