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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

Björn Fischer-Zirnsak, Nathalie Escande-Beillard, Jaya Ganesh, Yu Xuan Tan, Mohammed Al Bughaili, Angela E Lin, Inderneel Sahai, Paulina Bahena, Sara L Reichert, Abigail Loh, et al. (2015) AMERICAN JOURNAL OF HUMAN GENETICS. 97(3). p.483-492
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 P5 CS, 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ARTERIAL-TORTUOSITY-SYNDROME, ENCODING DELTA(1)-PYRROLINE-5-CARBOXYLATE SYNTHASE, PYCR1 MUTATIONS, BARSY-SYNDROME, PHENOTYPE, ALDH18A1, DISEASE, GENE, OSTEODYSPLASTICA, TROPOELASTIN
journal title
AMERICAN JOURNAL OF HUMAN GENETICS
Am. J. Hum. Genet.
volume
97
issue
3
pages
483 - 492
Web of Science type
Article
Web of Science id
000361084700011
JCR category
GENETICS & HEREDITY
JCR impact factor
10.794 (2015)
JCR rank
8/165 (2015)
JCR quartile
1 (2015)
ISSN
0002-9297
DOI
10.1016/j.ajhg.2015.08.001
language
English
UGent publication?
yes
classification
A1
additional info
the first two authors contributed equally to this work; also the last three authors contributed equally to this work
copyright statement
I have transferred the copyright for this publication to the publisher
id
7083824
handle
http://hdl.handle.net/1854/LU-7083824
date created
2016-02-12 13:36:42
date last changed
2016-12-19 15:47:12
@article{7083824,
  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 P5 CS, 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.},
  author       = {Fischer-Zirnsak, Bj{\"o}rn and Escande-Beillard, Nathalie and Ganesh, Jaya and Tan, Yu Xuan and Al Bughaili, Mohammed and Lin, Angela E and Sahai, Inderneel and Bahena, Paulina and Reichert, Sara L and Loh, Abigail and Wright, Graham D and Liu, Jaron and Rahikkala, Elisa and Pivnick, Eniko K and Choudhri, Asim F and Kr{\"u}ger, Ulrike and Zemojtel, Tomasz and van Ravenswaaij-Arts, Conny and Mostafavi, Roya and Stolte-Dijkstra, Irene and Symoens, Sofie and Pajunen, Leila and Al-Gazali, Lihadh and Meierhofer, David and Robinson, Peter N and Mundlos, Stefan and Villarroel, Camilo E and Byers, Peter and Masri, Amira and Robertson, Stephen P and Schwarze, Ulrike and Callewaert, Bert and Reversade, Bruno and Kornak, Uwe},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {ARTERIAL-TORTUOSITY-SYNDROME,ENCODING DELTA(1)-PYRROLINE-5-CARBOXYLATE SYNTHASE,PYCR1 MUTATIONS,BARSY-SYNDROME,PHENOTYPE,ALDH18A1,DISEASE,GENE,OSTEODYSPLASTICA,TROPOELASTIN},
  language     = {eng},
  number       = {3},
  pages        = {483--492},
  title        = {Recurrent de novo mutations affecting residue Arg138 of pyrroline-5-carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2015.08.001},
  volume       = {97},
  year         = {2015},
}

Chicago
Fischer-Zirnsak, Björn, Nathalie Escande-Beillard, Jaya Ganesh, Yu Xuan Tan, Mohammed Al Bughaili, Angela E Lin, Inderneel Sahai, et al. 2015. “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 97 (3): 483–492.
APA
Fischer-Zirnsak, B., Escande-Beillard, N., Ganesh, J., Tan, Y. X., Al Bughaili, M., Lin, A. E., Sahai, I., et al. (2015). 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, 97(3), 483–492.
Vancouver
1.
Fischer-Zirnsak B, Escande-Beillard N, Ganesh J, Tan YX, Al Bughaili M, Lin AE, et al. 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. 2015;97(3):483–92.
MLA
Fischer-Zirnsak, Björn, Nathalie Escande-Beillard, Jaya Ganesh, et al. “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 97.3 (2015): 483–492. Print.