The University of Southampton
University of Southampton Institutional Repository

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

Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa
Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa
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.
autosomal recessive cutis laxa, PYCR1, proline, mitochondria, segmental progeroid disorders
1096-7192
352-361
Dimopoulou, Aikaterini
72cc3056-b026-4e8b-be88-46d593383a80
Fischer, Björn
1c9639bb-f750-4c0d-8484-f6b142867f23
Gardeitchik, Thatjana
0ebce96b-59f0-470d-a3be-7a7d08d088d8
Schröter, Phillipe
f0e67d0d-936c-4f7f-9825-0a9348bf1721
Kayserili, Hülya
ca283a57-cf54-4605-b2ce-d3c5ad75cd6e
Schlack, Claire
74b565ae-e012-48b5-bc0f-03c743551bed
Li, Yun
fbe20681-3f5b-4187-95d8-3e678690e99b
Brum, Jaime Moritz
cb47963b-dd30-4012-800c-b6869f97d6f3
Barisic, Ingeborg
eecca9c6-6878-4b68-9b6c-ff0bbb3057ff
Castori, Marco
756ba17e-e599-4c76-979e-fcc20ce6d8ad
Spaich, Christiane
c64318a7-e01a-477e-b897-cf8957417e85
Fletcher, Elaine
aab43ef3-2b39-4a3e-96e7-2e5adb10e085
Mahayri, Zeina
7a25d9d8-ba48-4d82-ac92-0527fb9b5ed1
Bhat, Meenakshi
cf063466-e61b-4ee9-84d8-064141168d66
Girisha, Katta M.
2b10dcff-6a82-4ca6-bfc2-a17799e83e57
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Johnson, Diana
5144874c-5607-4f68-814a-eabe50a75bd4
Phadke, Shubha
9d5ba825-7331-4a87-8a35-297373735d30
Gupta, Neerja
650008b2-be77-4552-8b2e-fc3404df29b2
Simandlova, Martina
36b3e17d-71fa-4bb1-a9f5-2519d6064dd7
Kabra, Madhulika
2ac744bb-0a32-4730-b208-fa8db8b589b9
David, Albert
3cca5377-d92a-4c34-acc0-3ac4ccd00de1
Nijtmans, Leo
4d630821-e9dd-41ff-85b7-e2d19d65e691
Chitayat, David
58df0be6-ca8f-43a1-91b0-960b4bd27376
Tuysuz, Beyhan
401df90a-41e1-4342-855a-c805a1cf2ed5
Brancati, Francesco
7fc2279a-e5a2-466e-a5a4-058dc8c952a3
Mundlos, Stefan
ee6332cb-8570-432d-a73d-f750470e9e06
van Maldergem, Lionel
e07f6688-6c3c-4d0e-8507-935c480889de
Morava, Eva
670e54c1-fc63-4ce7-91eb-362bd2ed063e
Wollnik, Bernd
e22fec4f-772e-4749-9fae-201885f680e6
Kornak, Uwe
236a971a-5e32-4bc9-b5bf-4bef8756dd8f
Dimopoulou, Aikaterini
72cc3056-b026-4e8b-be88-46d593383a80
Fischer, Björn
1c9639bb-f750-4c0d-8484-f6b142867f23
Gardeitchik, Thatjana
0ebce96b-59f0-470d-a3be-7a7d08d088d8
Schröter, Phillipe
f0e67d0d-936c-4f7f-9825-0a9348bf1721
Kayserili, Hülya
ca283a57-cf54-4605-b2ce-d3c5ad75cd6e
Schlack, Claire
74b565ae-e012-48b5-bc0f-03c743551bed
Li, Yun
fbe20681-3f5b-4187-95d8-3e678690e99b
Brum, Jaime Moritz
cb47963b-dd30-4012-800c-b6869f97d6f3
Barisic, Ingeborg
eecca9c6-6878-4b68-9b6c-ff0bbb3057ff
Castori, Marco
756ba17e-e599-4c76-979e-fcc20ce6d8ad
Spaich, Christiane
c64318a7-e01a-477e-b897-cf8957417e85
Fletcher, Elaine
aab43ef3-2b39-4a3e-96e7-2e5adb10e085
Mahayri, Zeina
7a25d9d8-ba48-4d82-ac92-0527fb9b5ed1
Bhat, Meenakshi
cf063466-e61b-4ee9-84d8-064141168d66
Girisha, Katta M.
2b10dcff-6a82-4ca6-bfc2-a17799e83e57
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Johnson, Diana
5144874c-5607-4f68-814a-eabe50a75bd4
Phadke, Shubha
9d5ba825-7331-4a87-8a35-297373735d30
Gupta, Neerja
650008b2-be77-4552-8b2e-fc3404df29b2
Simandlova, Martina
36b3e17d-71fa-4bb1-a9f5-2519d6064dd7
Kabra, Madhulika
2ac744bb-0a32-4730-b208-fa8db8b589b9
David, Albert
3cca5377-d92a-4c34-acc0-3ac4ccd00de1
Nijtmans, Leo
4d630821-e9dd-41ff-85b7-e2d19d65e691
Chitayat, David
58df0be6-ca8f-43a1-91b0-960b4bd27376
Tuysuz, Beyhan
401df90a-41e1-4342-855a-c805a1cf2ed5
Brancati, Francesco
7fc2279a-e5a2-466e-a5a4-058dc8c952a3
Mundlos, Stefan
ee6332cb-8570-432d-a73d-f750470e9e06
van Maldergem, Lionel
e07f6688-6c3c-4d0e-8507-935c480889de
Morava, Eva
670e54c1-fc63-4ce7-91eb-362bd2ed063e
Wollnik, Bernd
e22fec4f-772e-4749-9fae-201885f680e6
Kornak, Uwe
236a971a-5e32-4bc9-b5bf-4bef8756dd8f

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 and Kornak, Uwe (2013) Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Molecular Genetics and Metabolism, 110 (3), 352-361. (doi:10.1016/j.ymgme.2013.08.009). (PMID:24035636)

Record type: Article

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.

This record has no associated files available for download.

More information

e-pub ahead of print date: 24 August 2013
Published date: November 2013
Keywords: autosomal recessive cutis laxa, PYCR1, proline, mitochondria, segmental progeroid disorders
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 357073
URI: http://eprints.soton.ac.uk/id/eprint/357073
ISSN: 1096-7192
PURE UUID: 7124d1f4-edb5-4bf3-b761-52defd00072e

Catalogue record

Date deposited: 26 Sep 2013 13:12
Last modified: 08 Jan 2022 18:02

Export record

Altmetrics

Contributors

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×