Mutations in PYCR1 cause cutis laxa with progeroid features

Bruno Reversade; Nathalie Escande-Beillard; Aikaterini Dimopoulou; Björn Fischer; Serene C. Chng; Yun Li; Mohammad Shboul; Puay Yoke Tham; Hülya Kayserili; Lihadh Al-Gazali; Monzer Shahwan; Francesco Brancati; Hane Lee; Brian D. O'Connor; Mareen Schmidt Von Kegler; Barry Merriman; Stanley F. Nelson; Amira Masri; Fawaz Alkazaleh; Deanna Guerra; Paola Ferrari; Arti Nanda; Anna Rajab; David Markie; Mary Gray; John Nelson; Arthur Grix; Annemarie Sommer; Ravi Savarirayan; Andreas R. Janecke; Elisabeth Steichen; David Sillence; Ingrid Haußer; Birgit Budde; Gudrun Nürnberg; Peter Nürnberg; Petra Seemann; Désirée Kunkel; Giovanna Zambruno; Bruno Dallapiccola; Markus Schuelke; Stephen Robertson; Hanan Hamamy; Bernd Wollnik; Lionel Van Maldergem; Stefan Mundlos; Uwe Kornak

doi:10.1038/ng.413

Mutations in PYCR1 cause cutis laxa with progeroid features

Bruno Reversade, Nathalie Escande-Beillard, Aikaterini Dimopoulou, Björn Fischer, Serene C. Chng, Yun Li, Mohammad Shboul, Puay Yoke Tham, Hülya Kayserili, Lihadh Al-Gazali, Monzer Shahwan, Francesco Brancati, Hane Lee, Brian D. O'Connor, Mareen Schmidt Von Kegler, Barry Merriman, Stanley F. Nelson, Amira Masri, Fawaz Alkazaleh, Deanna GuerraPaola Ferrari, Arti Nanda, Anna Rajab, David Markie, Mary Gray, John Nelson, Arthur Grix, Annemarie Sommer, Ravi Savarirayan, Andreas R. Janecke, Elisabeth Steichen, David Sillence, Ingrid Haußer, Birgit Budde, Gudrun Nürnberg, Peter Nürnberg, Petra Seemann, Désirée Kunkel, Giovanna Zambruno, Bruno Dallapiccola, Markus Schuelke, Stephen Robertson, Hanan Hamamy, Bernd Wollnik, Lionel Van Maldergem, Stefan Mundlos, Uwe Kornak

Research output: Contribution to journal › Article › peer-review

194 Scopus citations

Abstract

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. 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. © 2009 Nature America, Inc. All rights reserved.

Original language	English (US)
Pages (from-to)	1016-1021
Number of pages	6
Journal	Nature Genetics
Volume	41
Issue number	9
DOIs	https://doi.org/10.1038/ng.413
State	Published - Jan 1 2009
Externally published	Yes

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Reversade, B., Escande-Beillard, N., Dimopoulou, A., Fischer, B., Chng, S. C., Li, Y., Shboul, M., Tham, P. Y., Kayserili, H., Al-Gazali, L., Shahwan, M., Brancati, F., Lee, H., O'Connor, B. D., Kegler, M. S. V., Merriman, B., Nelson, S. F., Masri, A., Alkazaleh, F., ... Kornak, U. (2009). Mutations in PYCR1 cause cutis laxa with progeroid features. Nature Genetics, 41(9), 1016-1021. https://doi.org/10.1038/ng.413

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title = "Mutations in PYCR1 cause cutis laxa with progeroid features",

abstract = "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. 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. {\textcopyright} 2009 Nature America, Inc. All rights reserved.",

author = "Bruno Reversade and Nathalie Escande-Beillard and Aikaterini Dimopoulou and Bj{\"o}rn Fischer and Chng, {Serene C.} and Yun Li and Mohammad Shboul and Tham, {Puay Yoke} and H{\"u}lya Kayserili and Lihadh Al-Gazali and Monzer Shahwan and Francesco Brancati and Hane Lee and O'Connor, {Brian D.} and Kegler, {Mareen Schmidt Von} and Barry Merriman and Nelson, {Stanley F.} and Amira Masri and Fawaz Alkazaleh and Deanna Guerra and Paola Ferrari and Arti Nanda and Anna Rajab and David Markie and Mary Gray and John Nelson and Arthur Grix and Annemarie Sommer and Ravi Savarirayan and Janecke, {Andreas R.} and Elisabeth Steichen and David Sillence and Ingrid Hau{\ss}er and Birgit Budde and Gudrun N{\"u}rnberg and Peter N{\"u}rnberg and Petra Seemann and D{\'e}sir{\'e}e Kunkel and Giovanna Zambruno and Bruno Dallapiccola and Markus Schuelke and Stephen Robertson and Hanan Hamamy and Bernd Wollnik and {Van Maldergem}, Lionel and Stefan Mundlos and Uwe Kornak",

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Reversade, B, Escande-Beillard, N, Dimopoulou, A, Fischer, B, Chng, SC, Li, Y, Shboul, M, Tham, PY, Kayserili, H, Al-Gazali, L, Shahwan, M, Brancati, F, Lee, H, O'Connor, BD, Kegler, MSV, Merriman, B, Nelson, SF, Masri, A, Alkazaleh, F, Guerra, D, Ferrari, P, Nanda, A, Rajab, A, Markie, D, Gray, M, Nelson, J, Grix, A, Sommer, A, Savarirayan, R, Janecke, AR, Steichen, E, Sillence, D, Haußer, I, Budde, B, Nürnberg, G, Nürnberg, P, Seemann, P, Kunkel, D, Zambruno, G, Dallapiccola, B, Schuelke, M, Robertson, S, Hamamy, H, Wollnik, B, Van Maldergem, L, Mundlos, S & Kornak, U 2009, 'Mutations in PYCR1 cause cutis laxa with progeroid features', Nature Genetics, vol. 41, no. 9, pp. 1016-1021. https://doi.org/10.1038/ng.413

TY - JOUR

T1 - Mutations in PYCR1 cause cutis laxa with progeroid features

AU - Reversade, Bruno

AU - Escande-Beillard, Nathalie

AU - Dimopoulou, Aikaterini

AU - Fischer, Björn

AU - Chng, Serene C.

AU - Li, Yun

AU - Shboul, Mohammad

AU - Tham, Puay Yoke

AU - Kayserili, Hülya

AU - Al-Gazali, Lihadh

AU - Shahwan, Monzer

AU - Brancati, Francesco

AU - Lee, Hane

AU - O'Connor, Brian D.

AU - Kegler, Mareen Schmidt Von

AU - Merriman, Barry

AU - Nelson, Stanley F.

AU - Masri, Amira

AU - Alkazaleh, Fawaz

AU - Guerra, Deanna

AU - Ferrari, Paola

AU - Nanda, Arti

AU - Rajab, Anna

AU - Markie, David

AU - Gray, Mary

AU - Nelson, John

AU - Grix, Arthur

AU - Sommer, Annemarie

AU - Savarirayan, Ravi

AU - Janecke, Andreas R.

AU - Steichen, Elisabeth

AU - Sillence, David

AU - Haußer, Ingrid

AU - Budde, Birgit

AU - Nürnberg, Gudrun

AU - Nürnberg, Peter

AU - Seemann, Petra

AU - Kunkel, Désirée

AU - Zambruno, Giovanna

AU - Dallapiccola, Bruno

AU - Schuelke, Markus

AU - Robertson, Stephen

AU - Hamamy, Hanan

AU - Wollnik, Bernd

AU - Van Maldergem, Lionel

AU - Mundlos, Stefan

AU - Kornak, Uwe

N1 - Generated from Scopus record by KAUST IRTS on 2023-02-15

PY - 2009/1/1

Y1 - 2009/1/1

N2 - 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. 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. © 2009 Nature America, Inc. All rights reserved.

AB - 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. 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. © 2009 Nature America, Inc. All rights reserved.

UR - https://www.nature.com/articles/ng.413

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U2 - 10.1038/ng.413

DO - 10.1038/ng.413

M3 - Article

SN - 1061-4036

VL - 41

SP - 1016

EP - 1021

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Mutations in PYCR1 cause cutis laxa with progeroid features

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