2. Academic Validation
  3. Mutations in PYCR1 cause cutis laxa with progeroid features

Mutations in PYCR1 cause cutis laxa with progeroid features

  • Nat Genet. 2009 Sep;41(9):1016-21. doi: 10.1038/ng.413.
Bruno Reversade 1,  Nathalie Escande-Beillard,  Aikaterini Dimopoulou,  Björn Fischer,  Serene C Chng,  Yun Li,  Mohammad Shboul,  Puay-Yoke Tham,  Hülya Kayserili,  Lihadh Al-Gazali,  Monzer Shahwan,  Francesco Brancati,  Hane Lee,  Brian D O'Connor,  Mareen Schmidt-von Kegler,  Barry Merriman,  Stanley F Nelson,  Amira Masri,  Fawaz Alkazaleh,  Deanna Guerra,  Paola Ferrari,  Arti Nanda,  Anna Rajab,  David Markie,  Mary Gray,  John Nelson,  Arthur Grix,  Annemarie Sommer,  Ravi Savarirayan,  Andreas R Janecke,  Elisabeth Steichen,  David Sillence,  Ingrid Hausser,  Birgit Budde,  Gudrun Nürnberg,  Peter Nürnberg,  Petra Seemann,  Désirée Kunkel,  Giovanna Zambruno,  Bruno Dallapiccola,  Markus Schuelke,  Stephen Robertson,  Hanan Hamamy,  Bernd Wollnik,  Lionel Van Maldergem,  Stefan Mundlos,  Uwe Kornak
Affiliations

Affiliation

  • 1 Institute of Medical Biology, A*STAR, Singapore, Singapore. bruno@reversade.com
PMID: 19648921 DOI: 10.1038/ng.413
Abstract

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. 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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