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
-
- Molecular Sequence Data
- Mutation, Missense
- Intellectual Disability/genetics
- Infant, Newborn
- Agenesis of Corpus Callosum
- Base Sequence
- Polymorphism, Single Nucleotide
- Skin/cytology
- Skin/metabolism*
- Skin/ultrastructure
- Cutis Laxa/etiology*
- Cutis Laxa/genetics*
- Cutis Laxa/metabolism
- Female
- Humans
- Pedigree
- Pyrroline Carboxylate Reductases/genetics*
- Pyrroline Carboxylate Reductases/metabolism
- Physical Chromosome Mapping
- Mutation*
- Infant
- Homozygote
- Case-Control Studies
- Chromosomes, Human, Pair 17
- Consanguinity
- Genes, Recessive
- Male
- Fibroblasts/metabolism
- Gene Deletion
- Child, Preschool
- Genetic Markers
- Frameshift Mutation
- PubMed
- 19648921 Full text @ Nat. Genet.
Citation
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. (2009) Mutations in PYCR1 cause cutis laxa with progeroid features. Nature Genetics. 41(9):1016-1021.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping