title: Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals.
abstract: For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is a chromatin disorder characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS Here, we generated a Zbtb24 BTB domain deletion mouse and found that loss of functional Zbtb24 leads to early embryonic lethality. Transcriptome analysis identified Cdca7 as the top down-regulated gene in Zbtb24 homozygous mutant mESCs, which can be restored by ectopic ZBTB24 expression. We further demonstrate enrichment of ZBTB24 at the CDCA7 promoter suggesting that ZBTB24 can function as a transcription factor directly controlling Cdca7 expression. Finally, we show that this regulation is conserved between species and that CDCA7 levels are reduced in patients carrying ZBTB24 nonsense mutations. Together, our findings demonstrate convergence of the two ICF genes ZBTB24 and CDCA7 at the level of transcription.
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden 2300RC, The Netherlands.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden 2300RC, The Netherlands.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Thijssen
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden 2300RC, The Netherlands.|Department of Microbiology and Immunology, UCSF Diabetes Center, University of California San Francisco, San Francisco, CA 94143-0534, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: de Klerk
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden 2300RC, The Netherlands.
authors.forename: Kelly K D
authors.initials: KK
authors.lastname: Vonk
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden 2300RC, The Netherlands.|Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China and.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden 2300RC, The Netherlands.
authors.forename: Bianca
authors.initials: B
authors.lastname: den Hamer
authors.affiliation: Department of Pediatric Immunology, Dr Sami Ulus Maternity and Children's Research and Educational Hospital, Ankara 06080, Turkey.
authors.forename: Caner
authors.initials: C
authors.lastname: Aytekin
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden 2300RC, The Netherlands.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden 2300RC, The Netherlands, l.clemens-daxinger@lumc.nl.
authors.forename: Lucia
authors.initials: L
authors.lastname: Daxinger
mesh_terms: D000818:Animals; D018389:Codon, Nonsense / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D005145:Face / Q000002:abnormalities* / Q000503:physiopathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D000081207:Primary Immunodeficiency Diseases; D012097:Repressor Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics; D000097584:DNA Methyltransferase 3B
chemical_list: D018389:Codon, Nonsense; D004248:DNA (Cytosine-5-)-Methyltransferases; D004265:DNA Helicases; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000097584:DNA Methyltransferase 3B; C445325:CDCA7 protein, human; C560314:ZBTB24 protein, human; C412063:HELLS protein, human