Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa

Aikaterini Dimopoulou, Björn Fischer, Thatjana Gardeitchik, Phillipe Schröter, Hülya Kayserili, Claire Schlack, Yun Li, Jaime Moritz Brum, Ingeborg Barisic, Marco Castori, Christiane Spaich, Elaine Fletcher, Zeina Mahayri, Meenakshi Bhat, Katta M. Girisha, Katherine Lachlan, Diana Johnson, Shubha Phadke, Neerja Gupta, Martina SimandlovaMadhulika Kabra, Albert David, Leo Nijtmans, David Chitayat, Beyhan Tuysuz, Francesco Brancati, Stefan Mundlos, Lionel Van Maldergem, Eva Morava, Bernd Wollnik, Uwe Kornak

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)352-361
Number of pages10
JournalMolecular genetics and metabolism
Issue number3
StatePublished - Nov 2013


  • Autosomal recessive cutis laxa
  • Mitochondria
  • PYCR1
  • Proline
  • Segmental progeroid disorders

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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