Mutations in PYCR1 cause cutis laxa with progeroid features
Tarih
2009Yazar
O'Connor, Brian D.
Merriman, Barry
Nelson, Stanley F.
Masri, Amira
Alkazaleh, Fawaz
Guerra, Deanna
Ferrari, Paola
Nanda, Arti
Rajab, Anna
Markie, David
Gray, Mary
Nelson, John
Grix, Arthur
Sommer, Annemarie
Savarirayan, Ravi
Janecke, Andreas R.
Steichen, Elisabeth
Sillence, David
Hausser, Ingrid
Budde, Birgit
Nuernberg, Gudrun
Nuernberg, Peter
Seemann, Petra
Kunkel, Desiree
Zambruno, Giovanna
Dallapiccola, Bruno
Schuelke, Markus
Robertson, Stephen
Hamamy, Hanan
Wollnik, Bernd
Van Maldergem, Lionel
Mundlos, Stefan
Kornak, Uwe
Kayserili, Huelya
Reversade, Bruno
Escande-Beillard, Nathalie
Dimopoulou, Aikaterini
Fischer, Bjoern
Chng, Serene C.
Li, Yun
Shboul, Mohammad
Tham, Puay-Yoke
Al-Gazali, Lihadh
Shahwan, Monzer
Brancati, Francesco
Lee, Hane
Schmidt-von Kegler, Mareen
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Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation(1-3). Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high- throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.
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