title: Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating mmachc expression.
abstract: Mutations in HCFC1 (MIM300019), have been recently associated with cblX (MIM309541), an X-linked, recessive disorder characterized by multiple congenital anomalies including craniofacial abnormalities. HCFC1 is a transcriptional co-regulator that modulates the expression of numerous downstream target genes including MMACHC, but it is not clear how these HCFC1 targets play a role in the clinical manifestations of cblX. To begin to elucidate the mechanism by which HCFC1 modulates disease phenotypes, we have carried out loss of function analyses in the developing zebrafish. Of the two HCFC1 orthologs in zebrafish, hcfc1a and hcfc1b, the loss of hcfc1b specifically results in defects in craniofacial development. Subsequent analysis revealed that hcfc1b regulates cranial neural crest cell differentiation and proliferation within the posterior pharyngeal arches. Further, the hcfc1b-mediated craniofacial abnormalities were rescued by expression of human MMACHC, a downstream target of HCFC1 that is aberrantly expressed in cblX. Furthermore, we tested distinct human HCFC1 mutations for their role in craniofacial development and demonstrated variable effects on MMACHC expression in humans and craniofacial development in zebrafish. Notably, several individuals with mutations in either HCFC1 or MMACHC have been reported to have mild to moderate facial dysmorphia. Thus, our data demonstrates that HCFC1 plays a role in craniofacial development, which is in part mediated through the regulation of MMACHC expression.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: anita.quintana@ucdenver.edu.
authors.forename: Anita M
authors.initials: AM
authors.lastname: Quintana
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: elizabeth.geiger@ucdenver.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Geiger
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: nate.achilly@nih.gov.
authors.forename: Nate
authors.initials: N
authors.lastname: Achilly
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1B1. Electronic address: david.rosenblatt@mcgill.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Section of Genetics, University of Colorado, School of Medicine, Aurora, CO 80045, USA. Electronic address: ken.maclean@ucdenver.edu.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Maclean
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, CO 80045, USA. Electronic address: sally.stabler@ucdenver.edu.
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.affiliation: Department of Craniofacial Biology, School of Dental Medicine, University of Colorado, CO 80045, USA. Electronic address: kristin.artinger@ucdenver.edu.
authors.forename: Kristin B
authors.initials: KB
authors.lastname: Artinger
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: bruce.appel@ucdenver.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Appel
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Section of Genetics, University of Colorado, School of Medicine, Aurora, CO 80045, USA. Electronic address: tamim.shaikh@ucdenver.edu.
authors.forename: Tamim H
authors.initials: TH
authors.lastname: Shaikh
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D001934:Branchial Region / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002465:Cell Movement; D019902:Chondrocytes / Q000166:cytology; D019465:Craniofacial Abnormalities / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051863:Host Cell Factor C1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008822:Mice, Transgenic; D009154:Mutation; D009432:Neural Crest / Q000166:cytology / Q000502:physiology; D010088:Oxidoreductases; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology; D014805:Vitamin B 12 / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; C000594858:MMACHC protein, zebrafish; D029961:Zebrafish Proteins; C000594857:hcfc1a protein, zebrafish; D049452:Green Fluorescent Proteins; C508359:MMACHC protein, human; D010088:Oxidoreductases; D014805:Vitamin B 12
keywords: Cobalamin; Craniofacial defects; Facial dysmorphia; HCFC1; MMACHC