Paternal uniparental disomy 14 and related disorders: placental gene expression analyses and histological examinations.
Although recent studies in patients with paternal uniparental disomy 14 [upd(14)pat] and other conditions affecting the chromosome 14q32.2 imprinted region have successfully identified underlying epigenetic factors involved in the development of upd(14)pat phenotype, several matters, including regulatory mechanism(s) for RTL1 expression, imprinting status of DIO3 and placental histological characteristics, remain to be elucidated. We therefore performed molecular studies using fresh placental samples from two patients with upd(14)pat. We observed that RTL1 expression level was about five times higher in the placental samples of the two patients than in control placental samples, whereas DIO3 expression level was similar between the placental samples of the two patients and the control placental samples. We next performed histological studies using the above fresh placental samples and formalin-fixed and paraffin-embedded placental samples obtained from a patient with a maternally derived microdeletion involving DLK1, the-IG-DMR, the MEG3-DMR and MEG3. Terminal villi were associated with swollen vascular endothelial cells and hypertrophic pericytes, together with narrowed capillary lumens. DLK1, RTL1 and DIO3 proteins were specifically identified in vascular endothelial cells and pericytes, and the degree of protein staining was well correlated with the expression dosage of corresponding genes. These results suggest that RTL1as-encoded microRNA functions as a repressor of RTL1 expression, and argue against DIO3 being a paternally expressed gene. Furthermore, it is inferred that DLK1, DIO3 and, specially, RTL1 proteins, play a pivotal role in the development of vascular endothelial cells and pericytes.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Masayo
M
Kagami
Kentaro
K
Matsuoka
Toshiro
T
Nagai
Michiko
M
Yamanaka
Kenji
K
Kurosawa
Nobuhiro
N
Suzumori
Yoichi
Y
Sekita
Mami
M
Miyado
Keiko
K
Matsubara
Tomoko
T
Fuke
Fumiko
F
Kato
Maki
M
Fukami
Tsutomu
T
Ogata
D059786:Abnormal Karyotype; D002135:Calcium-Binding Proteins; D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D024182:Uniparental Disomy / Q000235:genetics*; D000096803:Imprinting Disorders
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C498907:MEG3 non-coding RNA, human; D008565:Membrane Proteins; D011257:Pregnancy Proteins; D062085:RNA, Long Noncoding; C579465:RTL1 protein, human