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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Loh, Abigail Escande-Beillard, Nathalie Villarroel, Camilo E. Al-Gazali, Lihadh Reichert, Sara L. Byers, Peter Reversade, Bruno Krüger, Ulrike Rahikkala, Elisa Symoens, Sofie Robinson, Peter N. Fischer-Zirnsak, Björn Bahena, Paulina Liu, Jaron Mundlos, Stefan Tan, Yu Xuan Callewaert, Bert Meierhofer, David Al Bughaili, Mohammed Van Ravenswaaij-arts, Conny Choudhri, Asim F. Lin, Angela E. Kornak, Uwe Zemojtel, Tomasz Schwarze, Ulrike Wright, Graham D. Robertson, Stephen P. Mostafavi, Roya Pajunen, Leila Stolte-Dijkstra, Irene Sahai, Inderneel Ganesh, Jaya Pivnick, Eniko K. Masri, Amira |
| Description | Country affiliation: Germany Author Affiliation: Fischer-Zirnsak B ( Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany); Escande-Beillard N ( Institute of Medical Biology, A(∗); Ganesh J ( Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.); Tan YX ( Institute of Medical Biology, A(∗); Al Bughaili M ( Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany.); Lin AE ( Medical Genetics and Metabolism, Mass General Hospital for Children, Boston, MA 02114, USA.); Sahai I ( Medical Genetics and Metabolism, Mass General Hospital for Children, Boston, MA 02114, USA.); Bahena P ( Departamento de Genética Humana, Instituto Nacional de Pediatría, Mexico City 19050, Mexico.); Reichert SL ( Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.); Loh A ( Institute of Molecular and Cellular Biology, A(∗); Wright GD ( Institute of Medical Biology, A(∗); Liu J ( Institute of Medical Biology, A(∗); Rahikkala E ( PEDEGO Research Group and Medical Research Center Oulu, University of Oulu and Department of Clinical Genetics, Oulu University Hospital, 90029 OYS Oulu, Finland.); Pivnick EK ( Department of Pediatrics, Division of Medical Genetics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.); Choudhri AF ( Department of Radiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA); Krüger U ( Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany.); Zemojtel T ( Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany); van Ravenswaaij-Arts C ( Department of Genetics, University Medical Center Groningen, University of Groningen, 9712 Groningen, the Netherlands.); Mostafavi R ( Department of Pediatrics, Division of Medical Genetics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.); Stolte-Dijkstra I ( Department of Genetics, University Medical Center Groningen, University of Groningen, 9712 Groningen, the Netherlands.); Symoens S ( Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.); Pajunen L ( PEDEGO Research Group and Medical Research Center Oulu, University of Oulu and Department of Clinical Genetics, Oulu University Hospital, 90029 OYS Oulu, Finland.); Al-Gazali L ( Departments of Pediatrics, Pathology, and Radiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates.); Meierhofer D ( Mass-Spectrometry Facility, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany.); Robinson PN ( Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany); Mundlos S ( Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany); Villarroel CE ( Departamento de Genética Humana, Instituto Nacional de Pediatría, Mexico City 19050, Mexico.); Byers P ( Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195-7470, USA.); Masri A ( Department of Pediatrics, Faculty of Medicine, University of Jordan, 11942 Amman, Jordan.); Robertson SP ( Department of Women's and Children's Health, University of Otago, 9016 Dunedin, New Zealand.); Schwarze U ( Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.); Callewaert B ( Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.); Reversade B ( Institute of Medical Biology, A(∗); Kornak U ( Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany) |
| 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. |
| ISSN | 00029297 |
| e-ISSN | 15376605 |
| DOI | 10.1016/j.ajhg.2015.08.001 |
| Journal | The American Journal of Human Genetics |
| Issue Number | 3 |
| Volume Number | 97 |
| Language | English |
| Publisher | Cell Press (on behalf of American Society of Human Genetics) |
| Publisher Date | 2015-09-03 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Corneal Opacity Genetics Pathology Cutis Laxa Intellectual Disability Mutation, Missense Ornithine-oxo-acid Transaminase Amino Acid Sequence Genes, Dominant Molecular Sequence Data Pedigree Proline Metabolism Sequence Alignment Sequence Analysis, Dna Skin Species Specificity Research Support, Non-u.s. Gov't Discipline Human Genetics |
| Content Type | Text |
| Resource Type | Article Case study |
| Subject | Genetics Genetics (clinical) |
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