PMID- 16280085
OWN - NLM
STAT- MEDLINE
DCOM- 20060413
LR  - 20181113
IS  - 1471-2164 (Electronic)
IS  - 1471-2164 (Linking)
VI  - 6
DP  - 2005 Nov 9
TI  - Genetic mapping of putative Chrna7 and Luzp2 neuronal transcriptional enhancers 
      due to impact of a transgene-insertion and 6.8 Mb deletion in a mouse model of 
      Prader-Willi and Angelman syndromes.
PG  - 157
AB  - BACKGROUND: Prader-Willi and Angelman syndrome (PWS and AS) patients typically 
      have an approximately 5 Mb deletion of human chromosome 15q11-q13, of opposite 
      parental origin. A mouse model of PWS and AS has a transgenic insertion-deletion 
      (TgPWS/TgAS) of chromosome 7B/C subsequent to paternal or maternal inheritance, 
      respectively. In this study, we define the deletion endpoints and examine the 
      impact on expression of flanking genes. RESULTS: Using molecular and cytological 
      methods we demonstrate that 13 imprinted and 11 non-imprinted genes are included 
      in the TgPWS/TgAS deletion. Normal expression levels were found in TgPWS brain 
      for genes extending 9.1- or 5.6-Mb centromeric or telomeric of the deletion, 
      respectively. Our molecular cytological studies map the proximal deletion 
      breakpoint between the Luzp2 and Siglec-H loci, and we show that overall mRNA 
      levels of Luzp2 in TgPWS and TgAS brain are significantly reduced by 17%. 
      Intriguingly, 5' Chrna7 shows 1.7-fold decreased levels in TgPWS and TgAS brain 
      whereas there is a > or =15-fold increase in expression in neonatal liver and 
      spleen of these mouse models. By isolating a Chrna7-Tg fusion transcript from 
      TgAS mice, we mapped the telomeric deletion breakpoint in Chrna7 intron 4. 
      CONCLUSION: Based on the extent of the deletion, TgPWS/TgAS mice are models for 
      PWS/AS class I deletions. Other than for the first gene promoters immediately 
      outside the deletion, since genes extending 5.6-9.1 Mb away from each end of the 
      deletion show normal expression levels in TgPWS brain, this indicates that the 
      transgene array does not induce silencing and there are no additional linked 
      rearrangements. Using gene expression, non-coding conserved sequence (NCCS) and 
      synteny data, we have genetically mapped a putative Luzp2 neuronal enhancer 
      responsible for approximately 33% of allelic transcriptional activity. The Chrna7 
      results are explained by hypothesizing loss of an essential neuronal 
      transcriptional enhancer required for approximately 80% of allelic Chrna7 
      promoter activity, while the Chrna7 promoter is upregulated in B lymphocytes by 
      the transgene immunoglobulin enhancer. The mapping of a putative Chrna7 neuronal 
      enhancer inside the deletion has significant implications for understanding the 
      transcriptional regulation of this schizophrenia-susceptibility candidate gene.
FAU - Stefan, Mihaela
AU  - Stefan M
AD  - Center for Neurobiology and Behavior, Department of Psychiatry, University of 
      Pennsylvania, Philadelphia, PA 19104, USA. Mihaela.Stefan@chp.edu
FAU - Claiborn, Kathryn C
AU  - Claiborn KC
FAU - Stasiek, Edyta
AU  - Stasiek E
FAU - Chai, Jing-Hua
AU  - Chai JH
FAU - Ohta, Tohru
AU  - Ohta T
FAU - Longnecker, Richard
AU  - Longnecker R
FAU - Greally, John M
AU  - Greally JM
FAU - Nicholls, Robert D
AU  - Nicholls RD
LA  - eng
GR  - ES10631/ES/NIEHS NIH HHS/United States
GR  - R01 CA093444/CA/NCI NIH HHS/United States
GR  - HD31491/HD/NICHD NIH HHS/United States
GR  - R01 ES010631/ES/NIEHS NIH HHS/United States
GR  - R01 CA062234/CA/NCI NIH HHS/United States
GR  - R01 DE013127/DE/NIDCR NIH HHS/United States
GR  - CA62234/CA/NCI NIH HHS/United States
GR  - CA93444/CA/NCI NIH HHS/United States
GR  - R01 CA073507/CA/NCI NIH HHS/United States
GR  - CA73507/CA/NCI NIH HHS/United States
GR  - R01 HD031491/HD/NICHD NIH HHS/United States
GR  - DE13127/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20051109
PL  - England
TA  - BMC Genomics
JT  - BMC genomics
JID - 100965258
RN  - 0 (Chrna7 protein, human)
RN  - 0 (Chrna7 protein, mouse)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Immunoglobulins)
RN  - 0 (Luzp2 protein, mouse)
RN  - 0 (Receptors, Nicotinic)
RN  - 0 (alpha7 Nicotinic Acetylcholine Receptor)
SB  - IM
MH  - Alleles
MH  - Angelman Syndrome/*genetics
MH  - Animals
MH  - Brain/metabolism
MH  - Centromere/ultrastructure
MH  - Chromosome Mapping/*methods
MH  - DNA-Binding Proteins/*genetics
MH  - Disease Models, Animal
MH  - *Enhancer Elements, Genetic
MH  - *Gene Deletion
MH  - Gene Expression Regulation
MH  - Gene Silencing
MH  - Genomic Imprinting
MH  - Immunoglobulins/metabolism
MH  - In Situ Hybridization, Fluorescence
MH  - Introns
MH  - Mice
MH  - Models, Genetic
MH  - Neurons/*metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Physical Chromosome Mapping
MH  - Prader-Willi Syndrome/*genetics
MH  - Promoter Regions, Genetic
MH  - Receptors, Nicotinic/*genetics
MH  - Schizophrenia/genetics
MH  - Telomere/ultrastructure
MH  - Tissue Distribution
MH  - Transcription, Genetic
MH  - *Transgenes
MH  - Up-Regulation
MH  - alpha7 Nicotinic Acetylcholine Receptor
PMC - PMC1322230
EDAT- 2005/11/11 09:00
MHDA- 2006/04/14 09:00
PMCR- 2005/11/09
CRDT- 2005/11/11 09:00
PHST- 2005/07/14 00:00 [received]
PHST- 2005/11/09 00:00 [accepted]
PHST- 2005/11/11 09:00 [pubmed]
PHST- 2006/04/14 09:00 [medline]
PHST- 2005/11/11 09:00 [entrez]
PHST- 2005/11/09 00:00 [pmc-release]
AID - 1471-2164-6-157 [pii]
AID - 10.1186/1471-2164-6-157 [doi]
PST - epublish
SO  - BMC Genomics. 2005 Nov 9;6:157. doi: 10.1186/1471-2164-6-157.