Mutations in PYCR1 cause cutis laxa with progeroid features.

Base Sequence; Case-Control Studies; Child, Preschool; Chromosomes, Human, Pair 17; Consanguinity; Corpus Callosum/abnormalities; Cutis Laxa/etiology/genetics/metabolism; Female; Fibroblasts/metabolism; Frameshift Mutation; Gene Deletion; Genes, Recessive; Genetic Markers; Homozygote; Humans; Infant; Infant, Newborn; Male; Mental Retardation/genetics; Molecular Sequence Data; Mutation; Mutation, Missense; Pedigree; Physical Chromosome Mapping; Polymorphism, Single Nucleotide; Pyrroline Carboxylate Reductases/genetics/metabolism; Skin/cytology/metabolism/ultrastructure

Abstract :

[en] 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.

Disciplines :

Genetics & genetic processes

Author, co-author :

Reversade, Bruno

Escande-Beillard, Nathalie

Dimopoulou, Aikaterini

Fischer, Bjorn

Chng, Serene C

Li, Yun

Shboul, Mohammad

Tham, Puay*-Yoke

Kayserili, Hulya

Al-Gazali, Lihadh

More authors (37 more)

Language :

English

Title :

Mutations in PYCR1 cause cutis laxa with progeroid features.

Publication date :

2009

Journal title :

Nature Genetics

ISSN :

1061-4036

eISSN :

1546-1718

Publisher :

Nature Publishing Group, New York, United States - New York

Volume :

Issue :

Pages :

1016-21

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 02 February 2010

Statistics

Number of views

90 (7 by ULiège)

Number of downloads

3 (3 by ULiège)

More statistics

Scopus citations^®

184

Scopus citations^®
without self-citations

144

OpenCitations

183

Bibliography

Rajab, A. et al. Geroderma osteodysplasticum hereditaria and wrinkly skin syndrome in 22 patients from Oman. Am. J. Med. Genet. A 146A, 965-976 (2008).
Morava, E. et al. Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation. Eur. J. Hum. Genet. 16, 28-35 (2008). (Pubitemid 350269236)
Guerra, D. et al. The De Barsy syndrome. J. Cutan. Pathol. 31, 616-624 (2004).
Zhang, M.C. et al. Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN). J. Biol. Chem. 274, 981-986 (1999).
Al-Gazali, L.I., Sztriha, L., Skaff, F. & Haas, D. Gerodermia osteodysplastica and wrinkly skin syndrome: are they the same? Am. J. Med. Genet. 101, 213-220 (2001). (Pubitemid 32565697)
Nanda, A. et al. Gerodermia osteodysplastica/wrinkly skin syndrome: report of three patients and brief review of the literature. Pediatr. Dermatol. 25, 66-71 (2008). (Pubitemid 351315456)
Hamamy, H., Masri, A. & Ajlouni, K. Wrinkly skin syndrome. Clin. Exp. Dermatol. 30, 590-592 (2005).
Sommer, A. Photo essay-geroderma osteodysplastica. Am. J. Med. Genet. C. Semin. Med. Genet. 145C, 291-292 (2007).
Kunze, J. et al. De Barsy syndrome-an autosomal recessive, progeroid syndrome. Eur. J. Pediatr. 144, 348-354 (1985). (Pubitemid 16194454)
Phang, J.M., Pandhare, J. & Liu, Y. The metabolism of proline as microenvironmental stress substrate. J. Nutr. 138, 2008S-2015S (2008).
Hagedorn, C.H. & Phang, J.M. Transfer of reducing equivalents into mitochondria by the interconversions of proline and delta 1-pyrroline-5- carboxylate. Arch. Biochem. Biophys. 225, 95-101 (1983).
Meng, Z. et al. Crystal structure of human pyrroline-5-carboxylate reductase. J. Mol. Biol. 359, 1364-1377 (2006). (Pubitemid 43903503)
Mitsubuchi, H., Nakamura, K., Matsumoto, S. & Endo, F. Inborn errors of proline metabolism. J. Nutr. 138, 2016S-2020S (2008).
Baumgartner, M.R. et al. Delta1-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline. Eur. J. Pediatr. 164, 31-36 (2005).
Bicknell, L.S. et al. A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5- carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome. Eur. J. Hum. Genet. 16, 1176-1186 (2008).
Baumgartner, M.R. et al. Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)- pyrroline-5-carboxylate synthase. Hum. Mol. Genet. 9, 2853-2858 (2000).
Van Maldergem, L. et al. Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type. Neurology 71, 1602-1608 (2008).
Hennies, H.C. et al. Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin. Nat. Genet. 40, 1410-1412 (2008).
Kornak, U. et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat. Genet. 40, 32-34 (2008).
Hucthagowder, V. et al. Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion, and cell survival. Hum. Mol. Genet. 18, 2149-2165 (2009).
Wallace, D.C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359-407 (2005).
Balaban, R.S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483-495 (2005).
D'Autreaux, B. & Toledano, M.B. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat. Rev. Mol. Cell Biol. 8, 813-824 (2007). (Pubitemid 47462134)
Krishnan, N., Dickman, M.B. & Becker, D.F. Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress. Free Radic. Biol. Med. 44, 671-681 (2008). (Pubitemid 351172717)
Knott, A.B., Perkins, G., Schwarzenbacher, R. & Bossy-Wetzel, E. Mitochondrial fragmentation in neurodegeneration. Nat. Rev. Neurosci. 9, 505-518 (2008).
Lee, S. et al. Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence. J. Biol. Chem. 282, 22977-22983 (2007). (Pubitemid 47267359)
O'Connell, J.R. & Weeks, D.E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet. 63, 259-266 (1998).
Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97-101 (2002).
Thiele, H. & Nurnberg, P. HaploPainter: a tool for drawing pedigrees with complex haplotypes. Bioinformatics 21, 1730-1732 (2005).
Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347-1363 (1996). (Pubitemid 26153846)
Duvezin-Caubet, S. et al. Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J. Biol. Chem. 281, 37972-37979 (2006). (Pubitemid 46042101)
Teramoto, S. et al. Hydrogen peroxide-induced apoptosis and necrosis in human lung fibroblasts: protective roles of glutathione. Jpn. J. Pharmacol. 79, 33-40 (1999). (Pubitemid 29060545)
Hofhaus, G., Shakeley, R.M. & Attardi, G. Use of polarography to detect respiration defects in cell cultures. Methods Enzymol. 264, 476-483 (1996). (Pubitemid 26089332)
Hensey, C. & Gautier, J. Programmed cell death during Xenopus development: a spatiotemporal analysis. Dev. Biol. 203, 36-48 (1998). (Pubitemid 28506661)
Sive, H., Grainger, R.M. & Harland, R.M. Early Development of Xenopus Laevis: A Laboratory Manual (Cold Spring Harbor Press, New York, 2000).