Dimopoulou, Aikaterini, Fischer, Bjorn, Gardeitchik, Thatjana, Schroeter, Phillipe, Kayserili, Hullya, Schlack, Claire, Li, Yun, Brum, Jaime Moritz, Barisic, Ingeborg, Castori, Marco ORCID: 0000-0002-6069-0993, Spaich, Christiane, Fletcher, Elaine, Mahayri, Zeina, Bhat, Meenakshi, Girisha, Katta M., Lachlan, Katherine, Johnson, Diana, Phadke, Shubha ORCID: 0000-0002-6624-082X, Gupta, Neerja, Simandlova, Martina, Kabra, Madhulika, David, Albert, Nijtmans, Leo, Chitayat, David, Tuysuz, Beyhan ORCID: 0000-0002-9620-5021, Brancati, Francesco, Mundlos, Stefan, Van Maldergem, Lionel ORCID: 0000-0001-8880-5214, Morava, Eva, Wollnik, Bernd and Kornak, Uwe (2013). Genotype phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Mol. Genet. Metab., 110 (3). S. 352 - 362. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1096-7206

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Abstract

Autosomal recessive cutis laxa type 2B (ARCL2B; OMIM # 612940) is a segmental progeroid disorder caused by mutations in PYCR1 encoding pyrroline-5-carboxylate reductase 1, which is part of the conserved proline de novo synthesis pathway. Here we describe 33 patients with PYCR1-related ARCL from 27 families with initial diagnoses varying between wrinkly skin syndrome, gerodermia osteodysplastica, De Barsy syndrome or more severe progeria syndromes. Given the difficult differential diagnosis of ARCL syndromes we performed a systematic comparison of clinical features of PYCR1-related ARCL. Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects. Corneal clouding or cataracts, athetoid movements, and finger contractures were rather rare features, but had a high predictive value. In our cohort we identified 20 different PYCR1 mutations of which seven were novel. Most of the mutations accumulated in exons 4 to 6. Missense alterations of highly conserved residues were most frequent followed by splice site changes and a single nonsense mutation. Analysis of genotype phenotype correlation revealed that patients with mutations in the first two exons had lower average clinical scores and absent or only mild intellectual disability. Structural analyses predicted interference with PYCR1 multimerization for a subset of missense mutations. These findings have implications for the clinics as well as the pathomechanism of PYCR1-related ARCL. (C) 2013 Elsevier Inc. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dimopoulou, AikateriniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, BjornUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardeitchik, ThatjanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeter, PhillipeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kayserili, HullyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlack, ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brum, Jaime MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barisic, IngeborgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Castori, MarcoUNSPECIFIEDorcid.org/0000-0002-6069-0993UNSPECIFIED
Spaich, ChristianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fletcher, ElaineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahayri, ZeinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bhat, MeenakshiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Girisha, Katta M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lachlan, KatherineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Phadke, ShubhaUNSPECIFIEDorcid.org/0000-0002-6624-082XUNSPECIFIED
Gupta, NeerjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simandlova, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kabra, MadhulikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
David, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nijtmans, LeoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chitayat, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tuysuz, BeyhanUNSPECIFIEDorcid.org/0000-0002-9620-5021UNSPECIFIED
Brancati, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mundlos, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Maldergem, LionelUNSPECIFIEDorcid.org/0000-0001-8880-5214UNSPECIFIED
Morava, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornak, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-473589
DOI: 10.1016/j.ymgme.2013.08.009
Journal or Publication Title: Mol. Genet. Metab.
Volume: 110
Number: 3
Page Range: S. 352 - 362
Date: 2013
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication: SAN DIEGO
ISSN: 1096-7206
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DELTA(1)-PYRROLINE-5-CARBOXYLATE SYNTHASE P5CS; BARSY SYNDROME; ALTERED GLYCOSYLATION; MISSENSE MUTATION; BRAIN DYSGENESIS; PYCR1 MUTATIONS; DEBRE TYPE; GENE; OSTEODYSPLASTICA; TRAFFICKINGMultiple languages
Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47358

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