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

• Published in: American journal of human genetics Vol. 97; no. 3; pp. 483 - 492
• Main Authors: 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 F., 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-09-2015; Cell Press; Elsevier
• Subjects: ALDH18A1; Amino Acid Sequence; Amino acids; Base Sequence; Corneal Opacity - genetics; Corneal Opacity - pathology; cutis laxa; Cutis Laxa - genetics; Cutis Laxa - pathology; De Barsy syndrome; Genes, Dominant - genetics; Genetic disorders; Humans; Intellectual Disability - genetics; Intellectual Disability - pathology; mitochondria; Molecular Sequence Data; Mutation; Mutation, Missense - genetics; Ornithine-Oxo-Acid Transaminase - genetics; P5CS; Pedigree; progeroid syndrome; Proline - metabolism; Proteins; PYCR1; pyrroline-5-carboxylate synthase; Sequence Alignment; Sequence Analysis, DNA; Skin - pathology; Species Specificity; P5CS; progeroid syndrome; cutis laxa; proline metabolism; mitochondria; pyrroline-5-carboxylate synthase; PYCR1; De Barsy syndrome; ALDH18A1
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2015.08.001

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.