2. Academic Validation
  3. Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

  • Am J Hum Genet. 2015 Sep 3;97(3):483-92. doi: 10.1016/j.ajhg.2015.08.001.
Björn Fischer-Zirnsak 1,  Nathalie Escande-Beillard 2,  Jaya Ganesh 3,  Yu Xuan Tan 2,  Mohammed Al Bughaili 4,  Angela E Lin 5,  Inderneel Sahai 5,  Paulina Bahena 6,  Sara L Reichert 3,  Abigail Loh 7,  Graham D Wright 2,  Jaron Liu 2,  Elisa Rahikkala 8,  Eniko K Pivnick 9,  Asim F Choudhri 10,  Ulrike Krüger 4,  Tomasz Zemojtel 11,  Conny van Ravenswaaij-Arts 12,  Roya Mostafavi 9,  Irene Stolte-Dijkstra 12,  Sofie Symoens 13,  Leila Pajunen 8,  Lihadh Al-Gazali 14,  David Meierhofer 15,  Peter N Robinson 16,  Stefan Mundlos 16,  Camilo E Villarroel 6,  Peter Byers 17,  Amira Masri 18,  Stephen P Robertson 19,  Ulrike Schwarze 20,  Bert Callewaert 13,  Bruno Reversade 21,  Uwe Kornak 22
Affiliations

Affiliations

  • 1 Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany; FG Development & Disease, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany.
  • 2 Institute of Medical Biology, A(∗)STAR, 138648 Singapore, Singapore.
  • 3 Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 4 Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany.
  • 5 Medical Genetics and Metabolism, Mass General Hospital for Children, Boston, MA 02114, USA.
  • 6 Departamento de Genética Humana, Instituto Nacional de Pediatría, Mexico City 19050, Mexico.
  • 7 Institute of Molecular and Cellular Biology, A(∗)STAR, 138648 Singapore, Singapore.
  • 8 PEDEGO Research Group and Medical Research Center Oulu, University of Oulu and Department of Clinical Genetics, Oulu University Hospital, 90029 OYS Oulu, Finland.
  • 9 Department of Pediatrics, Division of Medical Genetics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  • 10 Department of Radiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Le Bonheur Children's Hospital, Memphis, TN 38163, USA.
  • 11 Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany; Labor-Berlin, 13353 Berlin, Germany.
  • 12 Department of Genetics, University Medical Center Groningen, University of Groningen, 9712 Groningen, the Netherlands.
  • 13 Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
  • 14 Departments of Pediatrics, Pathology, and Radiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates.
  • 15 Mass-Spectrometry Facility, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany.
  • 16 Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany; FG Development & Disease, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany.
  • 17 Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195-7470, USA.
  • 18 Department of Pediatrics, Faculty of Medicine, University of Jordan, 11942 Amman, Jordan.
  • 19 Department of Women's and Children's Health, University of Otago, 9016 Dunedin, New Zealand.
  • 20 Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.
  • 21 Institute of Medical Biology, A(∗)STAR, 138648 Singapore, Singapore; Institute of Molecular and Cellular Biology, A(∗)STAR, 138648 Singapore, Singapore; Department of Paediatrics, National University of Singapore, 119077 Singapore, Singapore. Electronic address: bruno@reversade.com.
  • 22 Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany; FG Development & Disease, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany. Electronic address: uwe.kornak@charite.de.
PMID: 26320891 DOI: 10.1016/j.ajhg.2015.08.001
Abstract

Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling.

Keywords

ALDH18A1; De Barsy syndrome; P5CS; PYCR1; cutis laxa; mitochondria; progeroid syndrome; proline metabolism; pyrroline-5-carboxylate synthase.

Figures