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Mice with maternal duplication of proximal Chromosome 11 (MatDp(prox11)), where  Meg1/Grb10  is located, exhibit pre- and postnatal growth retardation. To elucidate the responsible imprinted gene for the growth abnormality, we examined the precise structure and regulatory mechanism of this imprinted region and generated novel model mice mimicking the pattern of imprinted gene expression observed in the MatDp(prox11) by deleting differentially methylated region of  Meg1/Grb10  ( Meg1 -DMR). It was found that  Cobl  and  Ddc , the neighboring genes of  Meg1/Grb10 , also comprise the imprinted region. We also found that the mouse-specific repeat sequence consisting of several CTCF-binding motifs in the  Meg1 -DMR functions as a silencer, suggesting that the  Meg1/Grb10  imprinted region adopted a different regulatory mechanism from the  H19/Igf2  region. Paternal deletion of the  Meg1 -DMR (+/ΔDMR) caused both upregulation of the maternally expressed  Meg1/Grb10  Type I in the whole body and  Cobl  in the yolk sac and loss of paternally expressed  Meg1/Grb10  Type II and  Ddc  in the neonatal brain and heart, respectively, demonstrating maternalization of the entire  Meg1/Grb10  imprinted region. We confirmed that the +/ΔDMR mice exhibited the same growth abnormalities as the MatDp(prox11) mice. Fetal and neonatal growth was very sensitive to the expression level of  Meg1/Grb10  Type I, indicating that the 2-fold increment of the  Meg1/Grb10  Type I is one of the major causes of the growth retardation observed in the MatDp(prox11) and +/ΔDMR mice. This suggests that the corresponding human  GRB10  Type I plays an important role in the etiology of Silver-Russell syndrome caused by partial trisomy of 7p11-p13.

human molecular genetics

Paternal deletion of  Meg1/Grb10  DMR causes maternalization of the  Meg1/Grb10  cluster in mouse proximal Chromosome 11 leading to severe pre- and postnatal growth retardation