title: 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.
authors.affiliation: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yamazawa
authors.forename: Masayo
authors.initials: M
authors.lastname: Kagami
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagai
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kondoh
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Onigata
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Maeyama
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Seiji
authors.initials: S
authors.lastname: Mizuno
authors.forename: Yoko
authors.initials: Y
authors.lastname: Miyoshi
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Reiko
authors.initials: R
authors.lastname: Horikawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D006130:Growth Disorders / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000502:physiology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010920:Placenta / Q000378:metabolism*; D010929:Placentation; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D013577:Syndrome; D055815:Young Adult
chemical_list: C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II