Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that arises from lack of expression of paternally inherited genes known to be imprinted and located in the chromosome 15q11-q13 region. PWS is considered the most common syndromal cause of life-threatening obesity and is estimated at 1 in 10,000 to 20,000 individuals. A de novo paternally derived chromosome 15q11-q13 deletion is the cause of PWS in about 70% of cases, and maternal disomy 15 accounts for about 25% of cases. The remaining cases of PWS result either from genomic imprinting defects (microdeletions or epimutations) of the imprinting centre in the 15q11-q13 region or from chromosome 15 translocations. Here, we describe the clinical presentation of PWS, review the current understanding of causative cytogenetic and molecular genetic mechanisms, and discuss future directions for research.

Our study indicates that individuals with TI deletion generally have more behavioral and psychological problems than individuals with the TII deletion or UPD. Four recently identified genes have been identified in the chromosome region between BP1 and BP2 with 1 of the genes (NIPA-1) expressed in mouse brain tissue but not thought to be imprinted. It may be important for brain development or function. These genes are deleted in individuals with TI deletion and are implicated in compulsive behavior and lower intellectual ability in individuals with TI versus TII.

The DNA-binding activity of the Zn finger protein metal response element-binding transcription factor 1 (MTF-1) was rapidly induced both in vivo in mouse Hepa cells, canine MDCK, and human HeLa cells after incubation in medium containing zinc and in vitro in whole-cell extracts to which zinc was added. Acquisition of DNA-binding capacity in the presence of free zinc was temperature and time dependent and did not occur at 4؇C. In contrast, activated MTF-1 binding to the metal response element occurred at 4؇C. After Zn activation, mouse MTF-1 binding activity was more sensitive to EDTA and was stabilized by DNA binding relative to the Zn finger transcription factor Sp1. After dilution of nuclear or whole-cell extracts from Zn-treated cells and incubation at 37؇C, mouse MTF-1 DNA-binding activity was no longer detected but could be completely reconstituted by the subsequent readdition of zinc. In vitro-synthesized, recombinant mouse MTF-1 displayed a similar, reversible temperature-and Zn-dependent activation of DNA-binding activity. Analysis of deletion mutants of recombinant MTF-1 suggests that the Zn finger domain is important for the Zn-dependent activation of DNA-binding capacity. Thus, mouse MTF-1 functions as a reversibly activated sensor of free zinc pools in the cell. (20,21), zinc homeostasis (6), and protection against oxidative stress (18). A hallmark of MT-I and MT-II genes is their transcriptional induction by heavy metals (i.e., zinc and cadmium) (1). Metal response elements (MREs) are essential for this induction, and these elements are present in multiple copies in the proximal promoters of MT genes. MREs were initially shown to mediate transcriptional response of MT genes to zinc and cadmium (30) and more recently to mediate, in part, the transcriptional response to oxidative stress (7,8). Metallothioneins (MT) constitute a conserved family of cysteine-rich heavy-metal-binding proteins (15). In the mouse, MT-I and MT-II display a wide tissue distribution and have been demonstrated to participate in detoxification of cadmiumA protein that binds specifically to MREs and transactivates MT gene expression, MRE-binding transcription factor 1 (MTF-1), has been identified in mouse and human cells (4, 29). MTF-1 is a Zn finger transcription factor in the Cys 2 His 2 family. Targeted disruption of both MTF-1 alleles in mouse embryonic stem cells demonstrated its essential role for basal as well as heavy-metal-induced MT gene expression (13). Despite progress in describing the genetics of MTF-1, less is known about mechanisms of activation of this transcription factor. Schaffner and colleagues reported that MTF-1 DNAbinding activity is constitutive in nuclear extracts and that increased MTF-1 activity is detected only several hours after Zn treatment of cultured cells (29, 32). Transiently and stably transfected cell lines that overexpress mouse MTF-1 display constitutively elevated MRE-driven reporter gene expression and an attenuated response to exogenous metals (13,25,29).The modest inducibility of MRE-d...