Abstract
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.
Highlights
The human genetic locus 15q11-q13 is subject to genomic imprinting that is controlled by a bipartite imprinting center (IC) [1]
Prader-Willi syndrome (PWS) (MIM 176270) is a complex neurogenetic disorder with a population prevalence of 1 in 10 000 to 50 000 [3,4,5] that is characterized by decreased fetal activity, muscular hypotonia, failure to thrive, short stature, obesity, mental retardation, and hypogonadotropic hypogonadism, for review, see [2,6]
If not all, small nucleolar RNA (snoRNA) are processed from a long, non-protein-coding RNA transcript designated U-UBE3A-ATS in human and large paternal non-protein-coding RNA (Lncat) in mouse [7,8,9]
Summary
The human genetic locus 15q11-q13 is subject to genomic imprinting that is controlled by a bipartite imprinting center (IC) [1]. If not all, snoRNAs are processed from a long, non-protein-coding RNA (npcRNA) transcript designated U-UBE3A-ATS in human and Lncat (large paternal nonprotein-coding RNA, encompassing Snurf-Snrpn and Ipw exons together with the Ube3a antisense transcript) in mouse [7,8,9]. In mouse the syntenic PWS/AS locus is located on chromosome 7C and contains all the aforementioned protein coding and non-protein-coding gene orthologs, except for the presence of protein-coding gene Frat 3 and absence of HBII-437 and HBII-438a/438b snoRNA genes (Figure 1C). Several mouse models for PWS have already been generated (Figure 1D) They can be divided into 3 groups: 1) transgenic mouse lines with disruptions of the PWS/AS locus; 2) mice with targeted elimination of the imprinting center (IC) controlling transcription of PWS genes, or targeted elimination of individual, single genes from the PWS locus; and 3) mice with uniparental paternal disomy (UPD) [10,11].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
