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

Fischer-Zirnsak, B., Escande-Beillard, N., Ganesh, J., Tan, Y. X., Bughaili, M. A., Lin, A. E., et al. (2015). Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa. The American Journal of Human Genetics, 97(3), 483-492. doi:10.1016/j.ajhg.2015.08.001.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-5E8E-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-5E8F-C
Genre: Journal Article

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 Creators:
Fischer-Zirnsak, Björn1, Author
Escande-Beillard, Nathalie , Author
Ganesh, Jaya , Author
Tan, Yu Xuan , Author
Bughaili, Mohammed Al , Author
Lin, Angela E., Author
Sahai, Inderneel , Author
Bahena, Paulina , Author
Reichert, Sara L. , Author
Loh, Abigail, Author
Wright, Graham D. , Author
Liu, Jaron, Author
Rahikkala, Elisa , Author
Pivnick, Eniko K. , Author
Choudhri, Asim F. , Author
Krüger, Ulrike, Author
Zemojtel, Tomasz , Author
van Ravenswaaij-Arts, Conny , Author
Mostafavi, Roya , Author
Stolte-Dijkstra, Irene , Author
Symoens, Sofie , AuthorPajunen, Leila , AuthorAl-Gazali, Lihadh , AuthorMeierhofer, David2, Author              Robinson, P. N.1, Author              Mundlos, Stefan1, Author              Villarroel, Camilo E. , Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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

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Language(s): eng - English
 Dates: 2015-08-272015-09-03
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.ajhg.2015.08.001
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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 97 (3) Sequence Number: - Start / End Page: 483 - 492 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1