title: Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa.
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.
authors: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany; FG Development & Disease, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany.
authors: Björn
authors: B
authors: Fischer-Zirnsak
authors: Institute of Medical Biology, A(∗)STAR, 138648 Singapore, Singapore.
authors: Nathalie
authors: N
authors: Escande-Beillard
authors: Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Jaya
authors: J
authors: Ganesh
authors: Institute of Medical Biology, A(∗)STAR, 138648 Singapore, Singapore.
authors: Yu Xuan
authors: YX
authors: Tan
authors: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany.
authors: Mohammed
authors: M
authors: Al Bughaili
authors: Medical Genetics and Metabolism, Mass General Hospital for Children, Boston, MA 02114, USA.
authors: Angela E
authors: AE
authors: Lin
authors: Medical Genetics and Metabolism, Mass General Hospital for Children, Boston, MA 02114, USA.
authors: Inderneel
authors: I
authors: Sahai
authors: Departamento de Genética Humana, Instituto Nacional de Pediatría, Mexico City 19050, Mexico.
authors: Paulina
authors: P
authors: Bahena
authors: Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Sara L
authors: SL
authors: Reichert
authors: Institute of Molecular and Cellular Biology, A(∗)STAR, 138648 Singapore, Singapore.
authors: Abigail
authors: A
authors: Loh
authors: Institute of Medical Biology, A(∗)STAR, 138648 Singapore, Singapore.
authors: Graham D
authors: GD
authors: Wright
authors: Institute of Medical Biology, A(∗)STAR, 138648 Singapore, Singapore.
authors: Jaron
authors: J
authors: Liu
authors: PEDEGO Research Group and Medical Research Center Oulu, University of Oulu and Department of Clinical Genetics, Oulu University Hospital, 90029 OYS Oulu, Finland.
authors: Elisa
authors: E
authors: Rahikkala
authors: Department of Pediatrics, Division of Medical Genetics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors: Eniko K
authors: EK
authors: Pivnick
authors: 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.
authors: Asim F
authors: AF
authors: Choudhri
authors: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany.
authors: Ulrike
authors: U
authors: Krüger
authors: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany; Labor-Berlin, 13353 Berlin, Germany.
authors: Tomasz
authors: T
authors: Zemojtel
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, 9712 Groningen, the Netherlands.
authors: Conny
authors: C
authors: van Ravenswaaij-Arts
authors: Department of Pediatrics, Division of Medical Genetics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors: Roya
authors: R
authors: Mostafavi
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, 9712 Groningen, the Netherlands.
authors: Irene
authors: I
authors: Stolte-Dijkstra
authors: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors: Sofie
authors: S
authors: Symoens
authors: PEDEGO Research Group and Medical Research Center Oulu, University of Oulu and Department of Clinical Genetics, Oulu University Hospital, 90029 OYS Oulu, Finland.
authors: Leila
authors: L
authors: Pajunen
authors: Departments of Pediatrics, Pathology, and Radiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates.
authors: Lihadh
authors: L
authors: Al-Gazali
authors: Mass-Spectrometry Facility, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany.
authors: David
authors: D
authors: Meierhofer
authors: 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.
authors: Peter N
authors: PN
authors: Robinson
authors: 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.
authors: Stefan
authors: S
authors: Mundlos
authors: Departamento de Genética Humana, Instituto Nacional de Pediatría, Mexico City 19050, Mexico.
authors: Camilo E
authors: CE
authors: Villarroel
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195-7470, USA.
authors: Peter
authors: P
authors: Byers
authors: Department of Pediatrics, Faculty of Medicine, University of Jordan, 11942 Amman, Jordan.
authors: Amira
authors: A
authors: Masri
authors: Department of Women's and Children's Health, University of Otago, 9016 Dunedin, New Zealand.
authors: Stephen P
authors: SP
authors: Robertson
authors: Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.
authors: Ulrike
authors: U
authors: Schwarze
authors: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors: Bert
authors: B
authors: Callewaert
authors: 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.
authors: Bruno
authors: B
authors: Reversade
authors: 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.
authors: Uwe
authors: U
authors: Kornak
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003318:Corneal Opacity / Q000235:genetics* / Q000473:pathology*; D003483:Cutis Laxa / Q000235:genetics* / Q000473:pathology*; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009953:Ornithine-Oxo-Acid Transaminase / Q000235:genetics*; D010375:Pedigree; D011392:Proline / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D012867:Skin / Q000473:pathology; D013045:Species Specificity
chemical_list: D011392:Proline; D009953:Ornithine-Oxo-Acid Transaminase
keywords: ALDH18A1; De Barsy syndrome; P5CS; PYCR1; cutis laxa; mitochondria; progeroid syndrome; proline metabolism; pyrroline-5-carboxylate synthase