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

American Journal of Human Genetics
Björn Fischer-ZirnsakUwe Kornak

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, affect...Continue Reading

References

Nov 1, 1985·European Journal of Pediatrics·J KunzeT Riebel
Mar 6, 2003·American Journal of Human Genetics·Dessislava MarkovaMon-Li Chu
Jun 16, 2005·The Journal of Investigative Dermatology·Zsolt UrbanElaine C Davis
Mar 19, 2008·American Journal of Medical Genetics. Part a·Anna RajabS Mundlos
Nov 11, 2008·Nature Genetics·Hans Christian HenniesStefan Mundlos
Mar 27, 2009·Human Molecular Genetics·Vishwanathan HucthagowderZsolt Urban
Apr 30, 2009·European Journal of Human Genetics : EJHG·Eva MoravaRon A Wevers
Aug 4, 2009·Nature Genetics·Bruno ReversadeUwe Kornak
Jan 22, 2010·Protein Science : a Publication of the Protein Society·Isabel Pérez-ArellanoJavier Cervera
Oct 19, 2010·American Journal of Medical Genetics. Part a·Beate AlbrechtEva Morava
Dec 15, 2010·Nature Chemical Biology·Zhihong ZhangYingming Zhao
Jan 5, 2011·American Journal of Medical Genetics. Part a·Yeşerin YildirimBeyhan Tüysüz
Mar 25, 2011·Journal of Inherited Metabolic Disease·Miski MohamedEva Morava
May 14, 2011·American Journal of Medical Genetics. Part a·Dar-Shong LinShuan-Pei Lin
Jul 9, 2011·American Journal of Medical Genetics. Part a·David L SkidmoreStephen P Robertson
Nov 29, 2011·Nucleic Acids Research·Samuel KerrienHenning Hermjakob
Dec 17, 2011·Biochimica Et Biophysica Acta·Dirk MossmannF-Nora Vögtle
Mar 14, 2012·American Journal of Medical Genetics. Part a·Stefania ZampattiFrancesco Brancati
Jun 30, 2012·Nature Methods·Johannes SchindelinAlbert Cardona
Jul 10, 2012·Human Genetics·Björn FischerUwe Kornak
Aug 22, 2013·European Journal of Human Genetics : EJHG·Thatjana GardeitchikEva Morava
Sep 17, 2013·Molecular Genetics and Metabolism·Aikaterini DimopoulouUwe Kornak
Apr 29, 2014·European Journal of Paediatric Neurology : EJPN : Official Journal of the European Paediatric Neurology Society·David F G J WolthuisEva Morava
Jun 11, 2014·Molecular Genetics and Metabolism·Björn FischerUwe Kornak
Nov 2, 2014·Journal of Proteome Research·Ina Gielisch, David Meierhofer
Apr 14, 2015·American Journal of Human Genetics·Tojo NakayamaGaneshwaran H Mochida
May 23, 2015·The Journal of Investigative Dermatology·Johannes EgererUwe Kornak
May 31, 2015·Brain : a Journal of Neurology·Marie CoutelierGiovanni Stevanin

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Citations

Apr 30, 2016·International Journal of Molecular Sciences·Ina Aretz, David Meierhofer
May 1, 2016·Annals of Neurology·Maha S ZakiJoseph G Gleeson
Sep 9, 2016·Journal of Human Genetics·Mohammed Al-BughailiBjörn Fischer-Zirnsak
Feb 24, 2017·Journal of Human Genetics·Priya T BholaDavid A Dyment
Dec 24, 2016·Neuropathology and Applied Neurobiology·M SchuelkeA Oldfors
May 9, 2018·International Journal of Molecular Sciences·Lavinia ArseniDonata Orioli
Sep 24, 2018·American Journal of Medical Genetics. Part a·Mathilde LefebvreChristel Thauvin-Robinet
Jun 13, 2017·Nature Communications·Laura S KremerHolger Prokisch
Oct 18, 2019·Antioxidants & Redox Signaling·Annekatrien BoelÉva Margittai
Feb 6, 2020·Journal of Inherited Metabolic Disease·Clara Marco-MarínVicente Rubio
Oct 12, 2019·Journal of Inherited Metabolic Disease·Lynne RumpingNanda M Verhoeven-Duif
Dec 11, 2019·Scientific Reports·Weiling XuSerpil C Erzurum
Jul 6, 2016·Clinical Dysmorphology·Atanu K DuttaSumita Danda
Jun 28, 2017·Journal of Inherited Metabolic Disease·T J de Koning
Jun 10, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Carlos R FerreiraNenad Blau
Aug 14, 2019·Annals of Clinical and Translational Neurology·Pamela MaginiEmanuele Panza
Jun 20, 2018·Journal of Human Genetics·Kishin KohUNKNOWN Japan Spastic Paraplegia Research Consortium
Oct 16, 2020·Clinical Genetics·Aude BeyensBert Callewaert
Jan 13, 2021·Ageing Research Reviews·Andrea Heinz
Dec 16, 2020·Journal of Inherited Metabolic Disease·Guido VogtBjörn Fischer-Zirnsak
Feb 11, 2021·Annual Review of Physiology·Weiling XuSerpil C Erzurum
Aug 31, 2021·Frontiers in Cell and Developmental Biology·Eduardo J PatriarcaGabriella Minchiotti

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