Expression and imprinting of MAGEL2 suggest a role in Prader-Willi syndrome and the homologous murine imprinting phenotype

Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinte d genes in chromosome 15q11-q13. Affected individuals exhibit neonatal hypo tonia, developmental delay and childhood-onset obesity. Necdin, a protein i mplicated in the terminal differentiation of neurons, is the only PWS candi date gene to reduce viability when disrupted in a mouse model, In this stud y, we have characterized MAGEL2 (also known as NDNL1), a gene with 51% amin o acid sequence similarity to necdin and located 41 kb distal to NDN in the PWS deletion region. MAGEL2 is expressed predominantly in brain, the prima ry tissue affected in PWS and in several fetal tissues as shown by northern blot analysis. MAGEL2 is imprinted with monoallelic expression in control brain, and paternal-only expression in the central nervous system as demons trated by its lack of expression in brain from a PWS-affected individual. T he orthologous mouse gene (Magel2) is located within 150 kb of Ndn, is impr inted with paternal-only expression and is expressed predominantly in late developmental stages and adult brain as shown by northern blotting, RT-PCR and whole-mount RNA in situ hybridization, Magel2 distribution partially ov erlaps that of Ndn, with strong expression being detected in the central ne rvous system in midgestation mouse embryos by in situ hybridization, We hyp othesize that, although loss of necdin expression may be important in the n eonatal presentation of PWS, loss of MAGEL2 may be critical to abnormalitie s in brain development and dysmorphic features in individuals with PWS.