In humans aging is invariably accompanied by changes in skin and bone. While age-related skin wrinkling is rather a cosmetic problem, age-related bone loss results in a increased susceptibility to fractures and thus a significant disease burden. To elucidate the molecular processes that govern aging in these tissues, we studied a group of recessively inherited diseases collectively characterized by the combination of wrinkly skin and osteoporotic bone. Over the last years we have been able to identify disease causing mutations in three different genes, two of which are involved in the Golgi network. Mutations in the a2 subunit of the vacuolar-type proton pump (H(+)-ATPase or V-ATPase) ATP6V0A2 were shown to be associated with wrinkly skin syndrome. This pump is present in Golgi secretory vesicles and appears to be important for the proper protein modification, as patients with mutations in the gene show abnormal serum protein glycosylation pattern. In a similar condition, geroderma osteodysplastica, we identified mutations in GORAB, a novel Rab6 interacting golgin. Through further mapping analysis we identified a third group of patients with overlapping wrinkly skin phenotypes and identified mutations in PYCR1, the gene coding for the enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline pyrroline-5-carboxylate reductase). Further investigation in vitro and in vivo (zebrafish, xenopus) showed that the enzyme is located exclusively in mitochondria and that inactivation resulted in increased rates of cell death. Our findings provide new insights into the molecular mechanisms of skin aging and osteoporosis. Proper function of the Golgi apparatus appears to be important for maintenance of healthy skin. Increased susceptibility to apoptosis may be an important trigger for age-related changes in skin and bone.

Selected publications

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.
Mutations in PYCR1 cause cutis laxa with progeroid features.
Nat Genet. 2009 Sep;41(9):1016-21.

Hucthagowder V, Morava E, Kornak U, Lefeber DJ, Fischer B, Dimopoulou A, Aldinger A, Choi J, Davis EC, Abuelo DN, Adamowicz M, Al-Aama J, Basel-Vanagaite L, Fernandez B, Greally MT, Gillessen-Kaesbach G, Kayserili H, Lemyre E, Tekin M, Türkmen S, Tuysuz B, Yüksel-Konuk B, Mundlos S, Van Maldergem L, Wevers RA, Urban Z.
Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival.
Hum Mol Genet. 2009 Jun 15;18(12):2149-65.

Hennies HC, Kornak U, Zhang H, Egerer J, Zhang X, Seifert W, Kühnisch J, Budde B, Nätebus M, Brancati F, Wilcox WR, Müller D, Kaplan PB, Rajab A, Zampino G, Fodale V, Dallapiccola B, Newman W, Metcalfe K, Clayton-Smith J, Tassabehji M, Steinmann B, Barr FA, Nürnberg P, Wieacker P, Mundlos S.
Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin.
Nat Genet. 2008 Dec;40(12):1410-2.

Kornak U, Reynders E, Dimopoulou A, van Reeuwijk J, Fischer B, Rajab A, Budde B, Nürnberg P, Foulquier F; ARCL Debré-type Study Group, Lefeber D, Urban Z, Gruenewald S, Annaert W, Brunner HG, van Bokhoven H, Wevers R, Morava E, Matthijs G, Van Maldergem L, Mundlos S.
Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2.
Nat Genet. 2008 Jan;40(1):32-4.