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

Content Provider	PubMed Central
Author	Björn, Fischer-zirnsak Escande-beillard, Nathalie Ganesh, Jaya Tan, Yu Xuan Al, Bughaili Md. Lin, Angela E. Sahai, Inderneel Bahena, Paulina Reichert, Sara L. Loh, Abigail Wright, Graham D. Liu, Jaron Elisa, Rahikkala Pivnick, Eniko K. Choudhri, Asim F. Krüger, Ulrike Tomasz, Zemojtel Van, Ravenswaaij-arts Conny Mostafavi, Roya Irene, Stolte-dijkstra Sofie, Symoens Pajunen, Leila Al-gazali, Lihadh Meierhofer, David Robinson, Peter N. Stefan, Mundlos Villarroel, Camilo E. Byers, Peter Masri, Amira Robertson, Stephen P. Schwarze, Ulrike Callewaert, Bert Bruno, Reversade Kornak, Uwe
Copyright Year	2015
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.
Related Links	http://dx.doi.org/10.1016/j.ajhg.2015.08.001
Ending Page	492
Page Count	10
Starting Page	483
File Format	PDF
ISSN	00029297
e-ISSN	15376605
Journal	American Journal of Human Genetics
Issue Number	3
Volume Number	97
Language	English
Publisher	Elsevier
Publisher Date	2015-09-01
Access Restriction	Open
Rights Holder	Elsevier
Subject Keyword	Genetics(clinical) Genetics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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