Deletion of the MBII-85 snoRNA Gene Cluster in Mice Results in Postnatal Growth Retardation
| Autor: | Boris V. Skryabin, Jana Pfeiffer, Jürgen Brosius, Sergej Handel, Leonid Gubar, Thomas Robeck, Birte Seeger, Elena Karpova, Timofey S. Rozhdestvensky |
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| Rok vydání: | 2007 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Cancer Research lcsh:QH426-470 Locus (genetics) Chromosomal translocation Biology Short stature Mice Chromosome 15 Gene cluster Genetics medicine Animals RNA Small Nucleolar Allele Molecular Biology Gene Growth Disorders Genetics (clinical) Ecology Evolution Behavior and Systematics Reverse Transcriptase Polymerase Chain Reaction Nucleic Acid Hybridization nutritional and metabolic diseases Gene targeting Genetics and Genomics Mus (Mouse) Blotting Northern Molecular biology Mice Inbred C57BL lcsh:Genetics Female medicine.symptom Gene Deletion Research Article |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 3, Iss 12, p e235 (2007) |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.0030235 |
| Popis: | Prader-Willi syndrome (PWS [MIM 176270]) is a neurogenetic disorder characterized by decreased fetal activity, muscular hypotonia, failure to thrive, short stature, obesity, mental retardation, and hypogonadotropic hypogonadism. It is caused by the loss of function of one or more imprinted, paternally expressed genes on the proximal long arm of chromosome 15. Several potential PWS mouse models involving the orthologous region on chromosome 7C exist. Based on the analysis of deletions in the mouse and gene expression in PWS patients with chromosomal translocations, a critical region (PWScr) for neonatal lethality, failure to thrive, and growth retardation was narrowed to the locus containing a cluster of neuronally expressed MBII-85 small nucleolar RNA (snoRNA) genes. Here, we report the deletion of PWScr. Mice carrying the maternally inherited allele (PWScrm−/p+) are indistinguishable from wild-type littermates. All those with the paternally inherited allele (PWScrm+/p−) consistently display postnatal growth retardation, with about 15% postnatal lethality in C57BL/6, but not FVB/N crosses. This is the first example in a multicellular organism of genetic deletion of a C/D box snoRNA gene resulting in a pronounced phenotype. Author Summary Prader-Willi syndrome, or PWS, is a complex neurogenetic disorder and the most common genetic cause of life-threatening childhood obesity. Newborns have poor muscle tone, making suckling difficult, which leads to poor weight gain. After infancy, they experience extreme hunger, leading to obesity. Other symptoms include short stature, mental retardation, and often infertility. In PWS patients, a complex set of genes on the paternal chromosome 15 (in the PWS region) is missing or unexpressed. In an attempt to understand this disorder, various protein-coding genes in this region have been deleted in mice, but none of the resulting phenotypes consistently correlated with the human disease. This region also contains a cluster of genes that encode functional non-protein-coding RNAs. We deleted specifically the MBII-85 small nucleolar RNA (snoRNA) gene cluster on the parental mouse chromosome, which did not affect expression of any of the other snoRNA or protein-coding genes in the PWS region. These mice consistently displayed postnatal growth retardation starting from day 5 to 6, low postnatal lethality only in certain genetic backgrounds ( |
| Databáze: | OpenAIRE |
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