title: Noncoding RNA-regulated gain-of-function of STOX2 in Finnish pre-eclamptic families.
abstract: The familial forms of early onset pre-eclampsia and related syndromes (HELLP) present with hypertension and proteinuria in the mother and growth restriction of the fetus. Genetically, these clinically similar entities are caused by different founder-dependent, placentally-expressed paralogous genes. All susceptibility genes (STOX1, lincHELLP, INO80B) identified so far are master control genes that regulate an essential trophoblast differentiation pathway, but act at different entry points. Many genes remain to be identified. Here we demonstrate that a long non-coding RNA (lncRNA) within intron 3 of the STOX2 gene on 4q35.1 acts as a permissive cis-acting regulator of alternative splicing of STOX2. When this lncRNA is mutated or absent, an alternative exon (3B) of STOX2 is included. This introduces a stop codon resulting in the deletion of a highly conserved domain of 64 amino acids in the C-terminal of the STOX2 protein. A mutation present within a regulatory region within intron 1 of STOX2 has the same effect after blocking with CRISPR technology: transcripts with exon 3B are upregulated. This proces appears related to transcriptional control by a chromatin-splicing adaptor complex as described for FGFR2. For STOX2, CHD5, coding for a chromodomain helicase DNA binding protein, qualifies as the chromatin modifier in this process.
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Cees Bm
authors.initials: CB
authors.lastname: Oudejans
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Ankie
authors.initials: A
authors.lastname: Poutsma
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Omar J
authors.initials: OJ
authors.lastname: Michel
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Thulluru
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: Mulders
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Henri J
authors.initials: HJ
authors.lastname: van de Vrugt
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Sistermans
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Marie
authors.initials: M
authors.lastname: van Dijk
mesh_terms: D017398:Alternative Splicing; D064113:CRISPR-Cas Systems; D002352:Carrier Proteins / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D010375:Pedigree; D010920:Placenta / Q000166:cytology / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D022661:RNA, Untranslated / Q000235:genetics*; D014327:Trophoblasts / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D022661:RNA, Untranslated; C000628072:STOX2 protein, human