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 Simandlova & 11 others Madhulika 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 journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)352-361
Number of pages10
JournalMolecular Genetics and Metabolism
Volume110
Issue number3
DOIs
Publication statusPublished - 11-2013

Fingerprint

Proline
Exons
Genotype
Phenotype
Mutation
Pyrroline Carboxylate Reductases
Skin
Oxidoreductases
Athetosis
Progeria
Genetic Databases
Defects
Muscle Hypotonia
Fetal Growth Retardation
Nonsense Codon
Genetic Association Studies
Contracture
Missense Mutation
Intellectual Disability
Cataract

All Science Journal Classification (ASJC) codes

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

Cite this

Dimopoulou, A., Fischer, B., Gardeitchik, T., Schröter, P., Kayserili, H., Schlack, C., ... Kornak, U. (2013). Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Molecular Genetics and Metabolism, 110(3), 352-361. https://doi.org/10.1016/j.ymgme.2013.08.009
Dimopoulou, Aikaterini ; Fischer, Björn ; Gardeitchik, Thatjana ; Schröter, Phillipe ; Kayserili, Hülya ; Schlack, Claire ; Li, Yun ; Brum, Jaime Moritz ; Barisic, Ingeborg ; Castori, Marco ; Spaich, Christiane ; Fletcher, Elaine ; Mahayri, Zeina ; Bhat, Meenakshi ; Girisha, Katta M. ; Lachlan, Katherine ; Johnson, Diana ; Phadke, Shubha ; Gupta, Neerja ; Simandlova, Martina ; Kabra, Madhulika ; David, Albert ; Nijtmans, Leo ; Chitayat, David ; Tuysuz, Beyhan ; Brancati, Francesco ; Mundlos, Stefan ; Van Maldergem, Lionel ; Morava, Eva ; Wollnik, Bernd ; Kornak, Uwe. / Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. In: Molecular Genetics and Metabolism. 2013 ; Vol. 110, No. 3. pp. 352-361.
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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.",
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Dimopoulou, A, Fischer, B, Gardeitchik, T, Schröter, P, Kayserili, H, Schlack, C, Li, Y, Brum, JM, Barisic, I, Castori, M, Spaich, C, Fletcher, E, Mahayri, Z, Bhat, M, Girisha, KM, Lachlan, K, Johnson, D, Phadke, S, Gupta, N, Simandlova, M, Kabra, M, David, A, Nijtmans, L, Chitayat, D, Tuysuz, B, Brancati, F, Mundlos, S, Van Maldergem, L, Morava, E, Wollnik, B & Kornak, U 2013, 'Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa', Molecular Genetics and Metabolism, vol. 110, no. 3, pp. 352-361. https://doi.org/10.1016/j.ymgme.2013.08.009

Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. / Dimopoulou, Aikaterini; Fischer, Björn; Gardeitchik, Thatjana; Schröter, Phillipe; Kayserili, Hülya; Schlack, Claire; Li, Yun; Brum, Jaime Moritz; Barisic, Ingeborg; Castori, Marco; Spaich, Christiane; Fletcher, Elaine; Mahayri, Zeina; Bhat, Meenakshi; Girisha, Katta M.; Lachlan, Katherine; Johnson, Diana; Phadke, Shubha; Gupta, Neerja; Simandlova, Martina; Kabra, Madhulika; David, Albert; Nijtmans, Leo; Chitayat, David; Tuysuz, Beyhan; Brancati, Francesco; Mundlos, Stefan; Van Maldergem, Lionel; Morava, Eva; Wollnik, Bernd; Kornak, Uwe.

In: Molecular Genetics and Metabolism, Vol. 110, No. 3, 11.2013, p. 352-361.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa

AU - Dimopoulou, Aikaterini

AU - Fischer, Björn

AU - Gardeitchik, Thatjana

AU - Schröter, Phillipe

AU - Kayserili, Hülya

AU - Schlack, Claire

AU - Li, Yun

AU - Brum, Jaime Moritz

AU - Barisic, Ingeborg

AU - Castori, Marco

AU - Spaich, Christiane

AU - Fletcher, Elaine

AU - Mahayri, Zeina

AU - Bhat, Meenakshi

AU - Girisha, Katta M.

AU - Lachlan, Katherine

AU - Johnson, Diana

AU - Phadke, Shubha

AU - Gupta, Neerja

AU - Simandlova, Martina

AU - Kabra, Madhulika

AU - David, Albert

AU - Nijtmans, Leo

AU - Chitayat, David

AU - Tuysuz, Beyhan

AU - Brancati, Francesco

AU - Mundlos, Stefan

AU - Van Maldergem, Lionel

AU - Morava, Eva

AU - Wollnik, Bernd

AU - Kornak, Uwe

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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.

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Dimopoulou A, Fischer B, Gardeitchik T, Schröter P, Kayserili H, Schlack C et al. Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Molecular Genetics and Metabolism. 2013 Nov;110(3):352-361. https://doi.org/10.1016/j.ymgme.2013.08.009