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, Graham D. Wright, Jaron Liu, Elisa Rahikkala, Eniko K. Pivnick, Asim Choudhri, Ulrike Krüger, Tomasz Zemojtel, Conny Van Ravenswaaij-Arts, Roya Mostafavi, Irene Stolte-Dijkstra & 14 others Sofie Symoens, Leila Pajunen, Lihadh Al-Gazali, David Meierhofer, Peter N. Robinson, Stefan Mundlos, Camilo E. Villarroel, Peter Byers, Amira Masri, Stephen P. Robertson, Ulrike Schwarze, Bert Callewaert, Bruno Reversade, Uwe Kornak

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1929
Pages (from-to)483-492
Number of pages10
JournalAmerican Journal of Human Genetics
Volume97
Issue number3
DOIs
StatePublished - Sep 3 2015

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Ornithine-Oxo-Acid Transaminase
Mutation
Proline
Pyrroline Carboxylate Reductases
Cutis Laxa
Genetic Counseling
Amino Acid Substitution
Autosomal Dominant Cutis Laxa
Electrophoresis
Fibroblasts
Gels
DNA

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Fischer-Zirnsak, B., Escande-Beillard, N., Ganesh, J., Tan, Y. X., Al Bughaili, M., Lin, A. E., ... Kornak, U. (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. [1929]. https://doi.org/10.1016/j.ajhg.2015.08.001

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa. / Fischer-Zirnsak, Björn; Escande-Beillard, Nathalie; Ganesh, Jaya; Tan, Yu Xuan; Al Bughaili, Mohammed; Lin, Angela E.; Sahai, Inderneel; Bahena, Paulina; Reichert, Sara L.; Loh, Abigail; Wright, Graham D.; Liu, Jaron; Rahikkala, Elisa; Pivnick, Eniko K.; Choudhri, Asim; Krüger, Ulrike; Zemojtel, Tomasz; Van Ravenswaaij-Arts, Conny; Mostafavi, Roya; Stolte-Dijkstra, Irene; Symoens, Sofie; Pajunen, Leila; Al-Gazali, Lihadh; Meierhofer, David; Robinson, Peter N.; Mundlos, Stefan; Villarroel, Camilo E.; Byers, Peter; Masri, Amira; Robertson, Stephen P.; Schwarze, Ulrike; Callewaert, Bert; Reversade, Bruno; Kornak, Uwe.

In: American Journal of Human Genetics, Vol. 97, No. 3, 1929, 03.09.2015, p. 483-492.

Research output: Contribution to journalArticle

Fischer-Zirnsak, B, Escande-Beillard, N, Ganesh, J, Tan, YX, Al Bughaili, M, Lin, AE, Sahai, I, Bahena, P, Reichert, SL, Loh, A, Wright, GD, Liu, J, Rahikkala, E, Pivnick, EK, Choudhri, A, Krüger, U, Zemojtel, T, Van Ravenswaaij-Arts, C, Mostafavi, R, Stolte-Dijkstra, I, Symoens, S, Pajunen, L, Al-Gazali, L, Meierhofer, D, Robinson, PN, Mundlos, S, Villarroel, CE, Byers, P, Masri, A, Robertson, SP, Schwarze, U, Callewaert, B, Reversade, B & Kornak, U 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, vol. 97, no. 3, 1929, pp. 483-492. https://doi.org/10.1016/j.ajhg.2015.08.001
Fischer-Zirnsak, Björn ; Escande-Beillard, Nathalie ; Ganesh, Jaya ; Tan, Yu Xuan ; Al Bughaili, Mohammed ; Lin, Angela E. ; Sahai, Inderneel ; Bahena, Paulina ; Reichert, Sara L. ; Loh, Abigail ; Wright, Graham D. ; Liu, Jaron ; Rahikkala, Elisa ; Pivnick, Eniko K. ; Choudhri, Asim ; Krüger, Ulrike ; Zemojtel, Tomasz ; Van Ravenswaaij-Arts, Conny ; Mostafavi, Roya ; Stolte-Dijkstra, Irene ; Symoens, Sofie ; Pajunen, Leila ; Al-Gazali, Lihadh ; Meierhofer, David ; Robinson, Peter N. ; Mundlos, Stefan ; Villarroel, Camilo E. ; Byers, Peter ; Masri, Amira ; Robertson, Stephen P. ; Schwarze, Ulrike ; Callewaert, Bert ; Reversade, Bruno ; Kornak, Uwe. / Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa. In: American Journal of Human Genetics. 2015 ; Vol. 97, No. 3. pp. 483-492.
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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 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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AU - Fischer-Zirnsak, Björn

AU - Escande-Beillard, Nathalie

AU - Ganesh, Jaya

AU - Tan, Yu Xuan

AU - Al Bughaili, Mohammed

AU - Lin, Angela E.

AU - Sahai, Inderneel

AU - Bahena, Paulina

AU - Reichert, Sara L.

AU - Loh, Abigail

AU - Wright, Graham D.

AU - Liu, Jaron

AU - Rahikkala, Elisa

AU - Pivnick, Eniko K.

AU - Choudhri, Asim

AU - Krüger, Ulrike

AU - Zemojtel, Tomasz

AU - Van Ravenswaaij-Arts, Conny

AU - Mostafavi, Roya

AU - Stolte-Dijkstra, Irene

AU - Symoens, Sofie

AU - Pajunen, Leila

AU - Al-Gazali, Lihadh

AU - Meierhofer, David

AU - Robinson, Peter N.

AU - Mundlos, Stefan

AU - Villarroel, Camilo E.

AU - Byers, Peter

AU - Masri, Amira

AU - Robertson, Stephen P.

AU - Schwarze, Ulrike

AU - Callewaert, Bert

AU - Reversade, Bruno

AU - Kornak, Uwe

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N2 - 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.

AB - 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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