Mol. Hum. Reprod. Advance Access originally published online on June 18, 2004
Molecular Human Reproduction 2004 10(8):589-598; doi:10.1093/molehr/gah080
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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
Departments of 1Clinical Chemistry and 2Clinical Genetics and Human Genetics, VU University Medical Center, 1081 HV Amsterdam, 3Department for Clinical Sciences of Companion Animals, Utrecht University, Utrecht, The Netherlands, 4Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Beppu City, Japan and 5Department of Obstetrics and Gynaecology, Lyell McEwin Hospital, Adelaide University, Adelaide, Australia
6 To whom correspondence should be addressed. Email: cbm.oudejans{at}vumc.nl
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.
Key words: chromosome 10/imprinting/molar pregnancy/pre-eclampsia/trophoblast
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