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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

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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.
Keywords
ARTERIAL-TORTUOSITY-SYNDROME, ENCODING DELTA(1)-PYRROLINE-5-CARBOXYLATE SYNTHASE, PYCR1 MUTATIONS, BARSY-SYNDROME, PHENOTYPE, ALDH18A1, DISEASE, GENE, OSTEODYSPLASTICA, TROPOELASTIN

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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.
@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},
}

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