We have identified three C͞D-box small nucleolar RNAs (snoRNAs) and one H͞ACA-box snoRNA in mouse and human. In mice, all four snoRNAs (MBII-13, MBII-52, MBII-85, and MBI-36) are exclusively expressed in the brain, unlike all other known snoRNAs. Two of the human RNA orthologues (HBII-52 and HBI-36) share this expression pattern, and the remainder, HBII-13 and HBII-85, are prevalently expressed in that tissue. In mice and humans, the brain-specific H͞ACA box snoRNA (MBI-36 and HBI-36, respectively) is intronencoded in the brain-specific serotonin 2C receptor gene. The three human C͞D box snoRNAs map to chromosome 15q11-q13, within a region implicated in the Prader-Willi syndrome (PWS), which is a neurogenetic disease resulting from a deficiency of paternal gene expression. Unlike other C͞D box snoRNAs, two snoRNAs, HBII-52 and HBII-85, are encoded in a tandemly repeated array of 47 or 24 units, respectively. In mouse the homologue of HBII-52 is processed from intronic portions of the tandem repeats. Interestingly, these snoRNAs were absent from the cortex of a patient with PWS and from a PWS mouse model, demonstrating their paternal imprinting status and pointing to their potential role in the etiology of PWS. Despite displaying hallmarks of the two families of ubiquitous snoRNAs that guide 2-O-ribose methylation and pseudouridylation of rRNA, respectively, they lack any telltale rRNA complementarity. Instead, brain-specific C͞D box snoRNA HBII-52 has an 18-nt phylogenetically conserved complementarity to a critical segment of serotonin 2C receptor mRNA, pointing to a potential role in the processing of this mRNA. T he biogenesis of eukaryotic ribosomes involves a complex rRNA processing pathway mostly taking place in a specialized subnuclear compartment, the nucleolus. Pre-rRNA maturation includes, in addition to a series of endonucleolytic and exonucleolytic cleavages, the covalent modification of a definite subset of rRNA nucleotides, essentially by 2Ј-O-ribose methylation and pseudouridylation. Each of these modifications is found at about 100 sites per vertebrate ribosome (1). Although these modifications are phylogenetically conserved and restricted to the most highly conserved and functionally important regions of rRNA, their function remains largely unknown. Spliceosomal small nuclear RNAs (snRNAs) also contain a number of conserved 2Ј-Omethylated nucleotides and pseudouridines, confined to snRNA sequences critical for splicing, i.e., involved in contacts with premRNA or other snRNAs (2). Remarkably, nucleotide modifications in the 5Ј terminal region of U2 snRNA are required for assembly of a functional U2 sn-ribonucleoprotein particle (3).The nucleolus contains a large number of small, metabolically stable RNAs, termed small nucleolar RNAs (snoRNAs) that fall into two major classes, the C͞D box and H͞ACA box snoRNAs, designated after common sequence motifs involved in the assembly of sno-ribonucleoprotein particles. Although each class includes a small number of snoRNAs required for definite pre-rRNA cl...

A subset of patients with Angelman and Prader-Willi syndrome have apparently normal chromosomes of biparental origin, but abnormal DNA methylation at several loci within chromosome 15q11-13, and probably have a defect in imprinting. Using probes from a newly established 160-kb contig including D15S63 (PW71) and SNRPN, we have identified inherited microdeletions in two AS families and three PWS families. The deletions probably affect a single genetic element that we term the 15q11-13 imprinting centre (IC). In our model, the IC regulates the chromatin structure, DNA methylation and gene expression in cis throughout 15q11-13. Mutations of the imprinting centre can be transmitted silently through the germline of one sex, but appear to block the resetting of the imprint in the germline of the opposite sex.

Angelman syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity. Angelman syndrome results from loss of function of the imprinted UBE3A (ubiquitin-protein ligase E3A) gene on chromosome 15q11.2-q13. This loss of function can be caused by a mutation on the maternal allele, a 5-7 Mb deletion of the maternally inherited chromosomal region, paternal uniparental disomy of chromosome 15, or an imprinting defect. The chromosomal deletion tends to cause the most severe symptoms, possibly owing to co-deletion of GABA receptor genes. UBE3A mutations and imprinting defects can be associated with a high risk of recurrence within families. Disruption of UBE3A function in neurons seems to inhibit synapse formation and experience-dependent synapse remodelling. Clinical diagnosis of Angelman syndrome in infants and young children is sometimes difficult, but can be verified by genetic tests. At present, treatment of symptoms such as seizures is the only medical strategy, but genetic therapies aimed at activating the silent copy of UBE3A on the paternal allele are conceivable.