Mutations in PYCR1 cause cutis laxa with progeroid features.
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.
Reversade
Bruno
B
Institute of Medical Biology, A*STAR, Singapore, Singapore. bruno@reversade.com
Escande-Beillard
Nathalie
N
Dimopoulou
Aikaterini
A
Fischer
Björn
B
Chng
Serene C
SC
Li
Yun
Y
Shboul
Mohammad
M
Tham
Puay-Yoke
PY
Kayserili
Hülya
H
Al-Gazali
Lihadh
L
Shahwan
Monzer
M
Brancati
Francesco
F
Lee
Hane
H
O'Connor
Brian D
BD
Schmidt-von Kegler
Mareen
M
Merriman
Barry
B
Nelson
Stanley F
SF
Masri
Amira
A
Alkazaleh
Fawaz
F
Guerra
Deanna
D
Ferrari
Paola
P
Nanda
Arti
A
Rajab
Anna
A
Markie
David
D
Gray
Mary
M
Nelson
John
J
Grix
Arthur
A
Sommer
Annemarie
A
Savarirayan
Ravi
R
Janecke
Andreas R
AR
Steichen
Elisabeth
E
Sillence
David
D
Hausser
Ingrid
I
Budde
Birgit
B
Nürnberg
Gudrun
G
Nürnberg
Peter
P
Seemann
Petra
P
Kunkel
Désirée
D
Zambruno
Giovanna
G
Dallapiccola
Bruno
B
Schuelke
Markus
M
Robertson
Stephen
S
Hamamy
Hanan
H
Wollnik
Bernd
B
Van Maldergem
Lionel
L
Mundlos
Stefan
S
Kornak
Uwe
U
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
D005819:Genetic Markers; D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase