Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci.
Genomic imprinting plays an important role in mammalian development. Loss of imprinting (LOI) through loss (LOM) or gain (GOM) of methylation is involved in many human disorders and cancers. The imprinted 11p15 region is crucial for the control of foetal growth and LOI at this locus is implicated in two clinically opposite disorders: Beckwith Wiedemann syndrome (BWS) with foetal overgrowth associated with an enhanced tumour risk and Russell-Silver syndrome (RSS) with intrauterine and postnatal growth restriction. So far, only a few studies have assessed multilocus LOM in human imprinting diseases. To investigate multilocus LOI syndrome, we studied the methylation status of five maternally and two paternally methylated loci in a large series (n = 167) of patients with 11p15-related foetal growth disorders. We found that 9.5% of RSS and 24% of BWS patients showed multilocus LOM at regions other than ICR1 and ICR2 11p15, respectively. Moreover, over two third of multilocus LOM RSS patients also had LOM at a second paternally methylated locus, DLK1/GTL2 IG-DMR. No additional clinical features due to LOM of other loci were found suggesting an (epi)dominant effect of the 11p15 LOM on the clinical phenotype for this series of patients. Surprisingly, four patients displayed LOM at both ICR1 and ICR2 11p15. Three of them had a RSS and one a BWS phenotype. Our results show for the first time that multilocus LOM can also concern RSS patients. Moreover, LOM can involve both paternally and maternally methylated loci in the same patient.
Azzi
Salah
S
Laboratoire d'Explorations Fonctionnelles Endocriniennes, APHP, Hôpital Armand Trousseau, INSERM UMR-S938 Team 4, Université Pierre et Marie Curie-Paris 6, Paris, France.
Rossignol
Sylvie
S
Steunou
Virginie
V
Sas
Theo
T
Thibaud
Nathalie
N
Danton
Fabienne
F
Le Jule
Maryline
M
Heinrichs
Claudine
C
Cabrol
Sylvie
S
Gicquel
Christine
C
Le Bouc
Yves
Y
Netchine
Irene
I
D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002135:Calcium-Binding Proteins; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D018392:Genomic Imprinting; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D017422:Sequence Analysis, DNA; D056730:Silver-Russell Syndrome / Q000235:genetics*
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C498907:MEG3 non-coding RNA, human; D008565:Membrane Proteins; D011506:Proteins; D062085:RNA, Long Noncoding