Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader–Willi syndrome mouse models

  title={Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader–Willi syndrome mouse models},
  author={F Ding and Yelena Prints and Madhu S. Dhar and Dabney K. Johnson and Carmen Garnacho-Montero and Robert D. Nicholls and Uta Francke},
  journal={Mammalian Genome},
Prader–Willi syndrome (PWS) is a neurobehavioral disorder caused by the lack of paternal expression of imprinted genes in the human chromosome region 15q11–13. Recent studies of rare human translocation patients narrowed the PWS critical genes to a 121-kb region containing PWCR1/HBII-85 and HBII-438 snoRNA genes. The existing mouse models of PWS that lack the expression of multiple genes, including Snrpn, Ube3a, and many intronic snoRNA genes, are characterized by 80%–100% neonatal lethality… 

Deletion of the MBII-85 snoRNA Gene Cluster in Mice Results in Postnatal Growth Retardation

This is the first example in a multicellular organism of genetic deletion of a C/D box snoRNA gene resulting in a pronounced phenotype of Prader-Willi syndrome, and it is reported the deletion of PWScr.

SnoRNA Snord116 (Pwcr1/MBII-85) Deletion Causes Growth Deficiency and Hyperphagia in Mice

Snord116del mice, the first snoRNA deletion animal model, reveal a novel role for a non-coding RNA in growth and feeding regulation in PWS and are revealed to maintain energy homeostasis by altered fuel usage.

Maternal transcription of non-protein coding RNAs from the PWS-critical region rescues growth retardation in mice

The results suggest that the lack of PWScr RNA expression in certain brain areas could be a primary cause of the growth retardation phenotype in mice and propose that activation of disease-associated genes on imprinted regions could lead to general therapeutic strategies in associated diseases.

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

Murine models of PWS unveiled the contribution of each affected gene to this multi-facetted disease, and also enabled the establishment of the minimal critical genomic region (PWScr) responsible for core symptoms, highlighting the importance of non-protein coding genes in the PWS locus.

Deletion of the Snord116/SNORD116 Alters Sleep in Mice and Patients with Prader-Willi Syndrome.

The study indicates that paternally expressed Snord116 is involved in the 24-h regulation of sleep physiological measures, suggesting that it is a candidate gene for the sleep disturbances that most individuals with PWS experience.

The Role of the Prader-Willi Syndrome Critical Interval for Epigenetic Regulation, Transcription and Phenotype

What is currently known of the molecular targets of SNORD116 and IPW is reviewed and their roles in contributing to the Prader-Willi Syndrome phenotype are disentangled.

Genomic analysis of the chromosome 15q11-q13 Prader-Willi syndrome region and characterization of transcripts for GOLGA8E and WHCD1L1 from the proximal breakpoint region

An updated version of a sequence-based physical map for a complex chromosomal region is presented, and the possibility of polymorphism in the genomic orientation of the BP1 to BP2 region is raised.

A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader–Willi syndrome

It is concluded that a deficiency of MKRN3, MAGEL2 and NDN is not sufficient to cause Prader–Willi syndrome, and two patients with PWS who have an atypical deletion on the paternal chromosome that does not include MKRN 3, MAGel2 andNDN are reported.

A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects.

Paternal inheritance of the human PWS-IC demonstrates for the first time that a positive regulatory element in the P WS-IC has diverged, and creates the first reported mouse model for AS imprinting defects.

Analysis of candidate imprinted genes in PWS subjects with atypical genetics: a possible inactivating mutation in the SNURF/SNRPN minimal promoter

Nine probands with a firm clinical diagnosis of PWS but who had neither a typical deletion in the PWS region nor UPD(15)mat were investigated for inactivating mutations, indicating that PWS may result from a stochastic partial inactivation of important genes.



Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader-Willi syndrome.

The data suggest the presence of a paternally expressed structural gene between SnRPN and Ipw whose deficiency causes lethality, although other possibilities exist, including position effects on expression of imprinted genes or that simultaneous deficiency of both ORFs of Snrpn causes lethalities.

A mouse model for Prader-Willi syndrome imprinting-centre mutations

It is indicated that the mouse is a suitable model system in which to investigate the molecular mechanisms of imprinting in the 15q11–q13 region, and both the position of the IC and its role in the coordinate expression of genes is conserved between mouse and human.

Exclusion of the C/D box snoRNA gene cluster HBII-52 from a major role in Prader–Willi syndrome

It is concluded that HBII-52 snoRNA genes do not play a major role in PWS, however, it cannot exclude the possibility that the loss of HBIi-52 has a phenotypic effect when accompanied by the Loss of function of other genes in 15q11–q13.

Evidence for the role of PWCR1/HBII-85 C/D box small nucleolar RNAs in Prader-Willi syndrome.

It is shown that the transcripts reported to be expressed in lymphoblast-somatic cell hybrids are not expressed in fibroblasts, and this hypothesis that loss of expression of the snoRNAs in the proposed minimal critical region confers much or all of the phenotype of PWS is consistent.

A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and angelman syndromes.

The characterization of a transgene insertion into mouse chromosome 7C of Epstein-Barr virus Latent Membrane Protein 2A, LMP2A, which has resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent is reported here.

Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization.

Three C/D-box small nucleolar RNAs (snoRNAs) and one H/ACA-box snoRNA in mouse and human are identified, demonstrating their paternal imprinting status and pointing to their potential role in the etiology of PWS.

Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes.

The chromosomal region, 15q11-q13, involved in Prader-Willi and Angelman syndromes (PWS and AS) represents a paradigm for understanding the relationships between genome structure, epigenetics,

Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15)(q27;q11.2) associated with Prader-Willi syndrome

It is concluded that PWCR1/HBII-85 snoRNAs is likely to play a major role in the PWS- phenotype and LINE and SINE sequences at the exchange points may have contributed to the translocation event.

A novel ATPase on mouse chromosome 7 is a candidate gene for increased body fat.

The unusual inheritance pattern of this phenotype suggests either genomic imprinting, known to occur in other local genes (Ube3a, Ipw), or an effect of maternal haploinsufficiency during pregnancy or lactation on body fat in the progeny.

The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A.

It is reported here that a processed antisense transcript of UBE3A starts at the IC, and the SNURF-SNRPN sense/UBE3A antisense transcription unit spans more than 460 kb and contains at least 148 exons, including the previously identified IPW exons.