A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome

Abstract

The Prader-Willi syndrome (PWS) is caused by a 5-6 Mbp de novo deletion on the paternal chromosome 15, maternal uniparental disomy 15 or an imprinting defect. All three lesions lead to the lack of expression of imprinted genes that are active on the paternal chromosome only: MKRN3, MAGEL2, NDN, C15orf2, SNURF-SNRPN and more than 70 C/D box snoRNA genes (SNORDs). The contribution to PWS of any of these genes is unknown, because no single gene mutation has been described so far. We report on two patients with PWS who have an atypical deletion on the paternal chromosome that does not include MKRN3, MAGEL2 and NDN. In one of these patients, NDN has a normal DNA methylation pattern and is expressed. In another patient, the paternal alleles of these genes are deleted as the result of an unbalanced translocation 45,X,der(X)t(X;15)(q28;q11.2). This patient is obese and mentally retarded, but does not have PWS. We conclude that a deficiency of MKRN3, MAGEL2 and NDN is not sufficient to cause PWS.

Figure 1

Physical map of 15q11–q13. Genes expressed from the maternal chromosome only are drawn as red boxes, genes expressed from the paternal chromosome only are drawn as blue boxes, snoRNA genes are indicated as blue vertical lines, genes expressed from both parental alleles are drawn as black boxes. The size of the deletions and localisation of the deletion breakpoints in patients 1, 2, 3 and PW93 are indicated below (black bars).

Figure 2

Photographs of the patients. (a) Patient 1 with the t(X;15)(q28;q11.2). (b) Patient 3 with PWS and an atypical deletion in 15q11–q13.

Figure 3

Schematic result of the cytogenetic analysis of the translocation in patient 1. Partial ideogram according to ISCN 2005; from left to right: normal chromosome 15, der(X) and chromosome X. The translocation breakpoints in 15q11 and Xq28 are indicated by a horizontal line.

Figure 4

Expression analysis in blood and lymphoblastoid cell line (LCL) RNA from patient 1 for exons 1–2 of SNURF-SNRPN. Compared with the normal control and the β-actin RT-PCR product no reduced SNURF-SNRPN expression level could be observed.

Figure 5

Methylation analysis of the NDN CpG island by SeQMA. Patient 3 shows a methylation pattern typical for PWS, whereas patient 2 shows a normal methylation pattern.

Figure 6

Expression analysis of NDN in RNA of lymphoblastoid cell line (LCL) RNA from patient 2.