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Nat Genet 2009 Sep 01;419:1016-21. doi: 10.1038/ng.413.
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Mutations in PYCR1 cause cutis laxa with progeroid features.

Reversade B , Escande-Beillard N , Dimopoulou A , Fischer B , Chng SC , Li Y , Shboul M , Tham PY , Kayserili H , Al-Gazali L , Shahwan M , Brancati F , Lee H , O'Connor BD , Schmidt-von Kegler M , Merriman B , Nelson SF , Masri A , Alkazaleh F , Guerra D , Ferrari P , Nanda A , Rajab A , Markie D , Gray M , Nelson J , Grix A , Sommer A , Savarirayan R , Janecke AR , Steichen E , Sillence D , Hausser I , Budde B , Nürnberg G , Nürnberg P , Seemann P , Kunkel D , Zambruno G , Dallapiccola B , Schuelke M , Robertson S , Hamamy H , Wollnik B , Van Maldergem L , Mundlos S , Kornak U .

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.

PubMed ID: 19648921
Article link: Nat Genet

Species referenced: Xenopus
Genes referenced: pycr1 tal1
GO keywords: proline metabolic process [+]
Morpholinos: Pycr1 MO1

Disease Ontology terms: autosomal recessive cutis laxa type IIB

Article Images: [+] show captions
References [+] :
Abecasis, Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. 2001, Pubmed