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.
authors: Institute of Medical Biology, A*STAR, Singapore, Singapore. bruno@reversade.com
authors: Bruno
authors: B
authors: Reversade
authors: Nathalie
authors: N
authors: Escande-Beillard
authors: Aikaterini
authors: A
authors: Dimopoulou
authors: Björn
authors: B
authors: Fischer
authors: Serene C
authors: SC
authors: Chng
authors: Yun
authors: Y
authors: Li
authors: Mohammad
authors: M
authors: Shboul
authors: Puay-Yoke
authors: PY
authors: Tham
authors: Hülya
authors: H
authors: Kayserili
authors: Lihadh
authors: L
authors: Al-Gazali
authors: Monzer
authors: M
authors: Shahwan
authors: Francesco
authors: F
authors: Brancati
authors: Hane
authors: H
authors: Lee
authors: Brian D
authors: BD
authors: O'Connor
authors: Mareen
authors: M
authors: Schmidt-von Kegler
authors: Barry
authors: B
authors: Merriman
authors: Stanley F
authors: SF
authors: Nelson
authors: Amira
authors: A
authors: Masri
authors: Fawaz
authors: F
authors: Alkazaleh
authors: Deanna
authors: D
authors: Guerra
authors: Paola
authors: P
authors: Ferrari
authors: Arti
authors: A
authors: Nanda
authors: Anna
authors: A
authors: Rajab
authors: David
authors: D
authors: Markie
authors: Mary
authors: M
authors: Gray
authors: John
authors: J
authors: Nelson
authors: Arthur
authors: A
authors: Grix
authors: Annemarie
authors: A
authors: Sommer
authors: Ravi
authors: R
authors: Savarirayan
authors: Andreas R
authors: AR
authors: Janecke
authors: Elisabeth
authors: E
authors: Steichen
authors: David
authors: D
authors: Sillence
authors: Ingrid
authors: I
authors: Hausser
authors: Birgit
authors: B
authors: Budde
authors: Gudrun
authors: G
authors: Nürnberg
authors: Peter
authors: P
authors: Nürnberg
authors: Petra
authors: P
authors: Seemann
authors: Désirée
authors: D
authors: Kunkel
authors: Giovanna
authors: G
authors: Zambruno
authors: Bruno
authors: B
authors: Dallapiccola
authors: Markus
authors: M
authors: Schuelke
authors: Stephen
authors: S
authors: Robertson
authors: Hanan
authors: H
authors: Hamamy
authors: Bernd
authors: B
authors: Wollnik
authors: Lionel
authors: L
authors: Van Maldergem
authors: Stefan
authors: S
authors: Mundlos
authors: Uwe
authors: U
authors: Kornak
mesh_terms: D061085:Agenesis of Corpus Callosum; D001483:Base Sequence; D016022:Case-Control Studies; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D003241:Consanguinity; D003483:Cutis Laxa / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D016368:Frameshift Mutation; D017353:Gene Deletion; D005808:Genes, Recessive; D005819:Genetic Markers; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D011762:Pyrroline Carboxylate Reductases / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D005819:Genetic Markers; D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase