Mutations in PYCR1 cause cutis laxa with progeroid features

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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 retardation1,2,3. 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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Figure 1: Phenotypic characteristics and genetic findings of subjects with PYCR1-related autosomal recessive cutis laxa with progeroid appearance.
Figure 2: Effect of PYCR1 mutations.
Figure 3: Loss of PYCR1 causes increased sensitivity to oxidative stress.
Figure 4: Phenotype of Pycr1 Xenopus morphants.
Figure 5: Skin hypoplasia in Pycr1 morphants is accompanied by spontaneous apoptosis and is independent of anemia.

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J. Common and B. Lane for advice and help with primary cultures. J. Gautier for TUNEL protocol. K. Rogers and S. Rogers for their help and advice on histology. This study was supported by the German Federal Ministry of Education and Research (BMBF) by grant 01GM0623 (SKELNET) to U.K. and S.M. and grants 01GM0880 and 01GM0801 to B.W., a grant from the Deutsche Forschungsgemeinschaft (Collaborative Research Centre 577) to U.K. and P.N., and by A*STAR and the Branco Weiss Foundation to B.R.

Author information

B.R., N.E.-B., S.M. and U.K. designed the study. H.K., L.A.-G., M. Shahwan, B.R., F.B., S.F.N., A.M., F.A., D.G., P.F., A.N., A.R., D.M., M.G., J.N., A.G., A.S., R.S., A.R.J., E.S., D.S., B.D., S.R., H.H., B.W. and L.v.M. made clinical diagnoses and collected clinical data and samples. B.R., B.M., A.D., G.N., B.F., Y.L., B.B., P.N. and B.W. conducted genotyping and linkage analysis. H.L., B.O., B.M. and S.N. performed genomic loci capture. B.R., N.E.-B., A.D., B.F., D.K., S.C., M.S., P.-Y.T. performed immunoblotting, immunostaining, TUNEL, and proline level and FACS analysis. B.R., N.E.-B. and S.C. performed Xenopus work, ISH and Pycr1 constructs. U.K., B.F., M.S.-v.K. and P.S. performed zebrafish work. B.F., U.K. and M. Schuelke performed respiratory chain measurements. I.H. and G.Z. were responsible for ultrastructural and histological analysis of skin biopsies. B.R., N.E.-B., S.M. and U.K. wrote the manuscript.

Correspondence to Bruno Reversade or Stefan Mundlos.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1–2 (PDF 3105 kb)

Supplementary Video 1

Movie of circulating red blood cells and beating heart in control tadpole at stage 30. (AVI 6648 kb)

Supplementary Video 2

Movie of beating heart in Pycr1 morphant tadpole at stage 30 despite absence of circulating red blood cells. (AVI 6648 kb)

Supplementary Video 3

Movie of shared blood circulation between Pycr1 morphant (top) and control tadpole (bottom) in parabiotic embryos at stage 45. (AVI 3715 kb)

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Reversade, B., Escande-Beillard, N., Dimopoulou, A. et al. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet 41, 1016–1021 (2009) doi:10.1038/ng.413

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