The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes.
We describe a screen for new imprinted human genes, and the identification in this way of ZAC (zinc finger protein which regulates apoptosis and cell cycle arrest)/ PLAGL1 (pleomorphicadenoma of the salivary gland gene like 1) as a strong candidate gene for transient neonatal diabetes mellitus (TNDM). To screen for imprinted genes, we compared parthenogenetic DNA from the chimeric patient FD and androgenetic DNA from hydatidiform mole, using restriction landmark genome scanning for methylation. This resulted in identification of two novel imprinted loci, one of which (NV149) we mapped to the TNDM region of 6q24. From analysis of the corresponding genomic region, it was determined that NV149 lies approximately 60 kb upstream of the ZAC / PLAGL1 gene. RT-PCR analysis was used to confirm that this ZAC / PLAGL1 is expressed only from the paternal allele in a variety of tissues. TNDM is known to result from upregulation of a paternally expressed gene on chromosome 6q24. The paternal expression, map position and known biological properties of ZAC / PLAGL1 make it highly likely that it is the TNDM gene. In particular, ZAC / PLAGL1 is a transcriptional regulator of the type 1 receptor for pituitary adenylate cyclase-activating polypeptide, which is the most potent known insulin secretagog and an important mediator of autocrine control of insulin secretion in the pancreatic islet.
Kamiya
M
M
CREST, Japan Science and Technology Corporation (JST), Genome Exploration Research Group, Genomic Sciences Center (GSC), Genome Science Laboratory and Biogenetic Research Center, Riken Tsukuba Life Science Center, Ibaraki, Japan.
Judson
H
H
Okazaki
Y
Y
Kusakabe
M
M
Muramatsu
M
M
Takada
S
S
Takagi
N
N
Arima
T
T
Wake
N
N
Kamimura
K
K
Satomura
K
K
Hermann
R
R
Bonthron
D T
DT
Hayashizaki
Y
Y
D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D020451:Contig Mapping; D018899:CpG Islands; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D008745:Methylation; D016133:Polymerase Chain Reaction; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015183:Restriction Mapping; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D016335:Zinc Fingers
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C106464:PLAGL1 protein, human; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins