title: A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability.
abstract: The discovery of mutations causing human disease has so far been biased toward protein-coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel resequencing of the nonrepetitive genomic linkage interval at Xq28 of family MRX3. We identified in the binding site of transcription factor YY1 a regulatory mutation that leads to overexpression of the chromatin-associated transcriptional regulator HCFC1. When tested on embryonic murine neural stem cells and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and a considerable reduction in neurite growth. Two other nonsynonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function.
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.
authors.forename: Lingli
authors.initials: L
authors.lastname: Huang
authors.forename: Lachlan A
authors.initials: LA
authors.lastname: Jolly
authors.forename: Saffron
authors.initials: S
authors.lastname: Willis-Owen
authors.forename: Alison
authors.initials: A
authors.lastname: Gardner
authors.forename: Raman
authors.initials: R
authors.lastname: Kumar
authors.forename: Evelyn
authors.initials: E
authors.lastname: Douglas
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Monika
authors.initials: M
authors.lastname: Cohen
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Corbett
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001665:Binding Sites; D002843:Chromatin / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D051863:Host Cell Factor C1 / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D022661:RNA, Untranslated / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014960:X Chromosome / Q000235:genetics; D050986:YY1 Transcription Factor / Q000235:genetics
chemical_list: D002843:Chromatin; C497692:HCFC1 protein, human; C497693:Hcfc1 protein, mouse; D051863:Host Cell Factor C1; D022661:RNA, Untranslated; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse