Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes.
Human chromosome 14q32.2 carries a cluster of imprinted genes including paternally expressed genes (PEGs) such as DLK1 and RTL1 and maternally expressed genes (MEGs) such as MEG3 (also known as GTL2), RTL1as (RTL1 antisense) and MEG8 (refs. 1,2), together with the intergenic differentially methylated region (IG-DMR) and the MEG3-DMR. Consistent with this, paternal and maternal uniparental disomy for chromosome 14 (upd(14)pat and upd(14)mat) cause distinct phenotypes. We studied eight individuals (cases 1-8) with a upd(14)pat-like phenotype and three individuals (cases 9-11) with a upd(14)mat-like phenotype in the absence of upd(14) and identified various deletions and epimutations affecting the imprinted region. The results, together with recent mouse data, imply that the IG-DMR has an important cis-acting regulatory function on the maternally inherited chromosome and that excessive RTL1 expression and decreased DLK1 and RTL1 expression are relevant to upd(14)pat-like and upd(14)mat-like phenotypes, respectively.
Kagami
Masayo
M
Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
Sekita
Yoichi
Y
Nishimura
Gen
G
Irie
Masahito
M
Kato
Fumiko
F
Okada
Michiyo
M
Yamamori
Shunji
S
Kishimoto
Hiroshi
H
Nakayama
Masahiro
M
Tanaka
Yukichi
Y
Matsuoka
Kentarou
K
Takahashi
Tsutomu
T
Noguchi
Mika
M
Tanaka
Yoko
Y
Masumoto
Kouji
K
Utsunomiya
Takeshi
T
Kouzan
Hiroko
H
Komatsu
Yumiko
Y
Ohashi
Hirofumi
H
Kurosawa
Kenji
K
Kosaki
Kenjirou
K
Ferguson-Smith
Anne C
AC
Ishino
Fumitoshi
F
Ogata
Tsutomu
T
D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D019457:Chromosome Breakage; D002883:Chromosomes, Human, Pair 14; D003198:Computer Simulation; D019175:DNA Methylation; D021901:DNA, Intergenic; D005220:Fathers; D005260:Female; D017353:Gene Deletion; D018392:Genomic Imprinting; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009035:Mothers; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D012045:Regulatory Sequences, Nucleic Acid; D024182:Uniparental Disomy / Q000235:genetics*
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D021901:DNA, Intergenic; D036341:Intercellular Signaling Peptides and Proteins; C498907:MEG3 non-coding RNA, human; D008565:Membrane Proteins; D011506:Proteins; D062085:RNA, Long Noncoding