Exclusion of the C/D box snoRNA gene cluster HBII-52 from a major role in Prader?Willi syndrome

Abstract

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurogenetic disorders caused by the loss of function of imprinted genes in 15q11-q13. The maternally expressed UBE3A gene is affected in AS. Four protein-encoding genes (MKRN3, MAGEL2, NDN and SNURF-SNRPN) and several small nucleolar (sno) RNA genes (HBII-13, HBII-436, HBII-85, HBII-438A, HBII-438B and HBII-52) are expressed from the paternal chromosome only but their contribution to PWS is unclear. To examine the role of the HBII-52 snoRNA genes, we have reinvestigated an AS family with a submicroscopic deletion spanning UBE3A and flanking sequences. By fine mapping of the centromeric deletion breakpoint in this family, we have found that the deletion affects all of the 47 HBII-52 genes. Since the complete loss of the HBII-52 genes in family members who carry the deletion on their paternal chromosome is not associated with an obvious clinical phenotype, we conclude that HBII-52 snoRNA genes do not play a major role in PWS. However, we cannot exclude the possibility that the loss of HBII-52 has a phenotypic effect when accompanied by the loss of function of other genes in 15q11-q13.

Prader-Willi syndrome

“…A crucial role for the SNORD115 locus was eliminated by an AS family with a familial microdeletion that included the entire SNORD115 gene cluster and the UBE3A locus. 103 There was no obvious phenotype when this microdeletion was passed paternally, but it resulted in AS when inherited maternally.…”

Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader–Willi syndrome

“…7,8,18,19 The multicopy snoRNA cluster SNORD115 (HBII-52) was ruled out as having a major role in PWS from analysis of a microdeletion that included the entire cluster and did not manifest an obvious clinical phenotype when the deletion was on the paternal chromosome. 20 Interestingly, SNORD115 snoRNA has now been shown to regulate alternative splicing of a serotonin receptor (5-HT 2C R). This apparently affects the expression of 5-HT 2C R isoforms in PWS patients that are different from those expressed in normal individuals, thus impacting a pathway with indirect but considerable influence on the PWS phenotype.…”

snoTARGET shows that human orphan snoRNA targets locate close to alternative splice junctions

“…There are at least two subtypes for deletion (Types I and II) and phenotypic differences exist among individuals with UPD, either Type I or Type II deletions (Bittel and Butler, 2005;Butler et al, 2004). Presumably, the lack of snoRNA expression is responsible for some of PWS's symptoms (Ding et al, 2005;Gallagher et al, 2002;Runte et al, 2005). A majority of snoRNAs within IC-SNURF-SNRPN are evolutionarily conserved in mammals (they are present in human, mouse, rat, and dog, yet in different copy numbers (Kishore and Stamm, 2006).…”