Mutations in PYCR1 cause cutis laxa with progeroid features

• Published in: Nature genetics Vol. 41; no. 9; pp. 1016 - 1021
• Main Authors: Reversade, Bruno, Escande-Beillard, Nathalie, Dimopoulou, Aikaterini, Fischer, Björn, Chng, Serene C, Li, Yun, Shboul, Mohammad, Tham, Puay-Yoke, Kayserili, Hülya, Al-Gazali, Lihadh, Shahwan, Monzer, Brancati, Francesco, Lee, Hane, O'Connor, Brian D, Kegler, Mareen Schmidt-von, Merriman, Barry, Nelson, Stanley F, Masri, Amira, Alkazaleh, Fawaz, Guerra, Deanna, Ferrari, Paola, Nanda, Arti, Rajab, Anna, Markie, David, Gray, Mary, Nelson, John, Grix, Arthur, Sommer, Annemarie, Savarirayan, Ravi, Janecke, Andreas R, Steichen, Elisabeth, Sillence, David, Haußer, Ingrid, Budde, Birgit, Nürnberg, Gudrun, Nürnberg, Peter, Seemann, Petra, Kunkel, Désirée, Zambruno, Giovanna, Dallapiccola, Bruno, Schuelke, Markus, Robertson, Stephen, Hamamy, Hanan, Wollnik, Bernd, Van Maldergem, Lionel, Mundlos, Stefan, Kornak, Uwe
• Format: Journal Article Web Resource
• Language: English
• Published: New York Nature Publishing Group US 01.09.2009; Nature Publishing Group
• Subjects: Agenesis of Corpus Callosum; Agriculture; Animal Genetics and Genomics; Apoptosis; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; Causes of; Child, Preschool; Chromosomes, Human, Pair 17; Consanguinity; Corpus Callosum/abnormalities; Cutis laxa; Cutis Laxa - etiology; Cutis Laxa - genetics; Cutis Laxa - metabolism; Cutis Laxa/etiology/genetics/metabolism; Danio rerio; delta-1-Pyrroline-5-Carboxylate Reductase; Enzymes; Female; Fibroblasts - metabolism; Frameshift Mutation; Freshwater; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Function; Gene mutations; Genes, Recessive; Genetic aspects; Genetic Markers; Genetics; Genetics & genetic processes; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Génétique & processus génétiques; Health aspects; Homozygote; Human Genetics; Human subjects; Humans; Infant; Infant, Newborn; Intellectual Disability - genetics; letter; Life sciences; Male; Medical research; Medical sciences; Medicine, Experimental; Mental Retardation/genetics; Molecular Sequence Data; Mutation; Mutation, Missense; Pedigree; Physical Chromosome Mapping; Polymorphism, Single Nucleotide; Proteins; Pyrroline Carboxylate Reductases - genetics; Pyrroline Carboxylate Reductases - metabolism; Pyrroline Carboxylate Reductases/genetics/metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sciences du vivant; Skin; Skin - cytology; Skin - metabolism; Skin - ultrastructure; Skin/cytology/metabolism/ultrastructure; Xenopus; Zebrafish; Singapore; Skin disease; Cutis laxa; Mutation; Elastic tissue disease; Systemic disease
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.413

Stefan Mundlos and colleagues report the identification of mutations in PYCR1 that cause autosomal recessive cutis laxa. PYCR1 encodes an enzyme involved in proline metabolism and localizes to mitochondria. Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation 1 , 2 , 3 . Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1 . We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.