International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

A3 A 2 Mb Imprinted Domain in Mouse Chromosome 7C Homologous to Human 15q11-q13 and Prader-Willi Syndrome

T. Ohta1, D. P. Locke1, T. A. Gray1, J. M. Gabriel1, E. M. Rinchik2, M. S. Dhar2 , D. K. Johnson2, Y. Ji1, M. T. C. Jong1, R. Longnecker3, B.T. Lamb1, R. D. Nicholls1. 1Department of Genetics, Case Western Reserve University, Cleveland, OH; 2Oak Ridge National Laboratory, Oak Ridge, TN; 3Northwestern University, Chicago, IL

Imprinted genes carry a gametic mark that results in differential expression of the maternally and paternally derived alleles during mammalian development. Prader-Willi (PWS) and Angelman (AS) syndromes result from a loss of function of paternally- or maternally-inherited genes, respectively, in chromosome 15q11-q13. This region contains an ~2 Mb imprinted domain, including several paternally and one maternally (UBE3A) expressed gene. Although UBE3A mutations cause AS, PWS is thought to be a multigenic disorder although the identity and number of genes involved is unknown. Furthermore, our analysis of mutations in the imprinting process in PWS and AS has defined an imprinting center (IC) that controls imprint switching throughout the imprinted domain during male and female gametogenesis. To facilitate the systematic analysis of this region we are developing relevant murine models.

The homologous region in the mouse maps to chromosome 7C, where we and others have defined a 2 Mb domain containing a series of paternally (Ipw, Ndn, Snurf, Snrpn, Zfp127, Zfp127as) and maternally-(Ube3a) expressed genes. The gene content, order (except for cen-tel orientation), and imprinted status are conserved in mouse and human. Recently, we have identified a novel gene located just centromeric of the PWS/AS deletions in human and the syntenic location in mouse, which shows biallelic expression in both species. The location of this non-imprinted gene defines one boundary of the imprinted domain. Further study of the interval between Zfp127, the closest imprinted gene, and the new gene will allow identification of epigenetic control elements that regulate the boundary of the PWS/AS imprinted domain.

We will also describe a transgene insertion in chromosome 7C that concomitantly deleted the entire PWS/AS-homologous imprinted and non-imprinted domains, but not closely flanking genes (Mlsn1, Igf1r). Paternal, but not maternal, inheritance of this transgene confers a lethal postnatal failure-to-thrive notably similar to PWS neonates and to other PWS mouse models. Segregation and imprint analyses of the transgene and homologous chromosome 7 provide evidence that replication asynchrony and homologous association are not part of the imprint establishment nor maintenance mechanisms. This heritable mouse line provides a rapid system to identify new imprinted genes, and can now be exploited to identify genes that contribute to the PWS phenotype by "transgene rescue" of the lethal and any subsequent phenotypes. Our initial results using cDNA, BAC and YAC Snurf-Snrpn transgenes will be presented.

Finally, we have shown that the IC spans the 5' end of a unique gene encoding two independent proteins (SNURF and SmN), that are translated from a single mRNA in all mouse and some human tissues. Polycistronic mRNAs therefore are encoded in mammalian genomes where they may form functional operons. Furthermore, phylogenetic evidence from five eutherian mammals provides strong evolutionary evidence for selection of the novel SNURF cistron for protein-coding function. Since SNURF is the only coding sequence within the IC, it may have provided the original selection for imprinting in this domain. Therefore, SNURF may function in early postnatal growth and vitality, and may be one gene contributing to the failure-to-thrive of PWS patients and mouse models. Combined, these studies will allow understanding of the regulation of large imprinted domains, genetic dissection of imprinted genes associated with specific PWS phenotypes, and provide insights for rational therapeutic approaches.

 


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