PUBLICATION

Mutations in PYCR1 cause cutis laxa with progeroid features

Authors
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., Merriman, B., Nelson, S.F., 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, A.R., Steichen, E., Sillence, D., Hauber, 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., and Kornak, U.
ID
ZDB-PUB-090807-9
Date
2009
Source
Nature Genetics   41(9): 1016-1021 (Journal)
Registered Authors
REVERSADE, Bruno
Keywords
none
MeSH Terms
  • Agenesis of Corpus Callosum
  • Base Sequence
  • Case-Control Studies
  • Child, Preschool
  • Chromosomes, Human, Pair 17
  • Consanguinity
  • Cutis Laxa/etiology*
  • Cutis Laxa/genetics*
  • Cutis Laxa/metabolism
  • Female
  • Fibroblasts/metabolism
  • Frameshift Mutation
  • Gene Deletion
  • Genes, Recessive
  • Genetic Markers
  • Homozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Intellectual Disability/genetics
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Pedigree
  • Physical Chromosome Mapping
  • Polymorphism, Single Nucleotide
  • Pyrroline Carboxylate Reductases/genetics*
  • Pyrroline Carboxylate Reductases/metabolism
  • Skin/cytology
  • Skin/metabolism*
  • Skin/ultrastructure
PubMed
19648921 Full text @ Nat. Genet.
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Errata and Notes