The mouse Zac1 locus: basis for imprinting and comparison with human ZAC.
We identified a maternally methylated CpG island at the mouse Zac1 locus on chromosome (Chr.) 10 in a screen for imprinted genes. The homologous human gene ZAC (also known as LOT1 and PLAGLI) is a candidate gene for transient neonatal diabetes (TNDM), an imprinted disorder associated with paternal duplication for 6q24 and characterized by intrauterine growth retardation and insulin dependence. A mouse model would be indispensable to investigate the basis of the disorder, however, there is apparently no similar phenotype in mice with the corresponding chromosome anomaly. To begin to understand this difference, we have undertaken a comparative analysis of the mouse and human genes. We show that the CpG island is far upstream of the coding body of mouse Zac1, that Zac1 transcripts initiate in a conserved region in the CpG island, and transcripts undergo complex splicing--all properties shared with the human gene. CpG island methylation is present in oocyte DNA and constitutes a germline-specific epigenetic mark. Mice with uniparental disomy (UPD) for Chr. 10 exhibit appropriate parent-of-origin dependent expression of Zac1, indicating that the absence of phenotypes comparable to aspects of human TNDM is not because imprinting of Zac1 is relaxed in these UPD mice.
Smith
Rachel J
RJ
Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK.
Arnaud
Philippe
P
Konfortova
Galia
G
Dean
Wendy L
WL
Beechey
Colin V
CV
Kelsey
Gavin
G
D024506:5' Flanking Region / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D005091:Exons; D015870:Gene Expression; D005796:Genes / Q000235:genetics; D016147:Genes, Tumor Suppressor; D018392:Genomic Imprinting; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins; D024182:Uniparental Disomy
D018797:Cell Cycle Proteins; C106464:PLAGL1 protein, human; C498423:Plagl1 protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins