Molecular and clinical findings and their correlations in Silver-Russell syndrome: implications for a positive role of IGF2 in growth determination and differential imprinting regulation of the IGF2–H19 domain in bodies and placentas

Abstract

Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features and is frequently caused by hypomethylation (epimutation) of the H19-DMR. Although molecular and clinical studies have extensively been performed for SRS patients themselves, such studies have not been carried out for placentas. We identified 20 epimutation-positive and 40 epimutation-negative Japanese SRS patients and obtained placental weight data from 12 epimutation-positive and ten epimutation-negative patients and paraffin-embedded placental tissues for molecular and histological examinations from three epimutation-positive and two epimutation-negative patients. Methylation patterns were comparable between leukocytes and placentas in both epimutation-positive and epimutation-negative patients. Epimutations resulted in virtually no IGF2 expression and biallelic slight H19 expression in the leukocytes and obviously reduced IGF2 expression of paternal origin and nearly normal H19 expression of maternal origin in the placentas. Epimutation-positive patients had characteristic body phenotype and small placentas with hypoplastic chorionic villi, and epimutation-negative patients had somewhat small placentas with hypoplastic chorionic villi or massive infarction. Furthermore, significant correlations were identified between the H19-DMR methylation index and the body and placental sizes and between the placental weight and the body size in the epimutation-positive patients, whereas such correlations were not detected for the head circumference. These results suggest (1) characteristic phenotype and reduced IGF2 expression in the epimutation-positive placentas; (2) similarities and differences in the epigenetic control of the IGF2-H19 domain between leukocytes and placentas; (3) a positive role of the IGF2 expression level, as reflected by the methylation index, in the determination of body and placental growth in epimutation-positive patients, except for the brain where IGF2 is expressed biallelically; (4) involvement of placental dysfunction in prenatal growth failure; and (5) relevance of both (epi)genetic factor(s) and environmental factor(s) to SRS in epimutation-negative patients.

Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver–Russell syndrome phenotypes

“…In a mouse model in which H19 was deleted and Igf2 expression was increased, both the placenta and the fetus were overgrown at E19 (35,36). In humans, placental growth defects are common in individuals with BWS and SRS (24,37). We observed that H19 +/hIC1 placentas not only are smaller, but also have abnormal placental morphology.…”

“…Because H19 +/hIC1 embryos display similar phenotypes to those of many patients with SRS who present with IC1 hypomethylation, including altered H19 and Igf2 expression and growth defects (23,24), we hypothesized that these embryos can serve as a model for SRS. Placental growth defects are prevalent among individuals with SRS (24); thus, we further characterized H19 +/hIC1 placentas to study potential mechanisms underlying SRS associated with IC1 hypomethylation.…”

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

“…46 Epigenetic abnormalities are detected in up to 35-65% of patients, the most frequent one being hypomethylation of the H19 ICR (Table 1). [46][47][48][49][50][51][52] Like BWS cases, a proportion of patients with Silver-Russell syndrome show hypomethylation at multiple ICRs (Table 1). 43,53 Moreover, over two-third of such patients have hypomethylation not only at the maternally methylated ICRs but also at another paternally methylated ICR at the DLK1-MEG3 locus (IG-DMR) ( Table 1).…”

Androgenetic/biparental mosaicism in a girl with Beckwith–Wiedemann syndrome-like and upd(14)pat-like phenotypes

“…We first performed bisulfite sequencing for the H19-DMR (differentially methylated region) and KvDMR1 as a screening of BWS 11,12 and that for the IG-DMR and the MEG3-DMR as a screening of upd (14)pat, 10 using leukocyte genomic DNA. Paternally derived clones were predominantly identified for the four DMRs examined ( Figure 1a).…”