The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas.
By affected sib-pair linkage analysis of 24 families with pre-eclampsia, we confirm a susceptibility locus on chromosome 10q22.1 in Dutch females: a multipoint non-parametric linkage score of 3.6 near marker D10S1432 was obtained. Haplotype analysis showed a parent-of-origin effect: maximal allele sharing in the affected sibs was found for maternally derived alleles in all families, but not for the paternally derived alleles. As matrilineal inheritance suggests the presence of maternally expressed imprinted genes, while imprinting operates predominantly in (extra)embryonic tissues, all genes (n=132) known on 10q22 between GATA121A08 and D10S580 were screened for seven sequence-related features associated with imprinting and subsequently tested for expression in first trimester placenta. Placental expression of genes selected in this way (n=55) was compared with expression in androgenetic placentas of identical gestational age. Two regions on 10q22 were identified with developmentally co-repressed genes with non-random chromosomal distribution. Interestingly, these two clusters, near CTNNA3 and KCNMA1 and each containing five genes with down-regulated expression in androgenetic placentas, coincided with the regions with maximal maternal allele sharing seen in the pre-eclamptic sisters. Our linkage and expression data are compatible with the concept that pre-eclampsia involves maternally expressed imprinted genes that operate in the first trimester placenta.
Oudejans
Cees B M
CB
Departments of Clinical Chemistry and Clinical Genetics and Human Genetics, VU University Medical Center, 1081 HV Amsterdam. cbm.oudejans@vumc.nl
Mulders
Joyce
J
Lachmeijer
Augusta M A
AM
van Dijk
Marie
M
Könst
Andrea A M
AA
Westerman
Bart A
BA
van Wijk
Inge J
IJ
Leegwater
Peter A J
PA
Kato
Hidenori D
HD
Matsuda
Takao
T
Wake
Norio
N
Dekker
Gustaaf A
GA
Pals
Gerard
G
ten Kate
Leo P
LP
Blankenstein
Marinus A
MA
D000483:Alleles; D000818:Animals; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D006239:Haplotypes; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics; D008297:Male; D051379:Mice; D010375:Pedigree; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy