title: EFTUD2 deficiency in vertebrates: Identification of a novel human mutation and generation of a zebrafish model.
abstract: BACKGROUND
  Congenital microphthalmia and coloboma are severe developmental defects that are frequently associated with additional systemic anomalies and display a high level of genetic heterogeneity.
  
  
  METHODS
  To identify the pathogenic variant in a patient with microphthalmia, coloboma, retinal dystrophy, microcephaly, and other features, whole exome sequencing analysis of the patient and parental samples was undertaken. To further explore the identified variant/gene, expression and functional studies in zebrafish were performed.
  
  
  RESULTS
  Whole exome sequencing revealed a de novo variant, c.473_474delGA, p.(Arg158Lysfs*4), in EFTUD2 which encodes a component of the spliceosome complex. Dominant mutations in EFTUD2 cause Mandibulofacial Dysostosis, Guion-Almeida type, which does not involve microphthalmia, coloboma, or retinal dystrophy; analysis of genes known to cause these ocular phenotypes identified several variants of unknown significance but no causal alleles in the affected patient. Zebrafish eftud2 demonstrated high sequence conservation with the human gene and broad embryonic expression. TALEN-mediated disruption was employed to generate a c.378_385 del, p.(Ser127Aspfs*23) truncation mutation in eftud2. Homozygous mutants displayed a reduced head size, small eye, curved body, and early embryonic lethality. Apoptosis assays demonstrated a striking increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells in the developing brain, eye, spinal cord, and other tissues starting at 30 hours postfertilization.
  
  
  CONCLUSIONS
  This study reports a novel mutation in EFTUD2 in a Mandibulofacial Dysostosis, Guion-Almeida type patient with unusual ocular features and the generation of a first animal model of eftud2 deficiency. The severe embryonic phenotype observed in eftud2 mutants indicates an important conserved role during development of diverse tissues in vertebrates.
authors.affiliation: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.|Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Brett
authors.initials: B
authors.lastname: Deml
authors.affiliation: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Reis
authors.affiliation: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Sanaa
authors.initials: S
authors.lastname: Muheisen
authors.affiliation: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
authors.forename: David
authors.initials: D
authors.lastname: Bick
authors.affiliation: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.|Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Semina
mesh_terms: D000818:Animals; D002675:Child, Preschool; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics; D005260:Female; D006801:Humans; D023421:Models, Animal; D009154:Mutation; D010445:Peptide Elongation Factors / Q000235:genetics*; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000235:genetics*; D015027:Zebrafish
chemical_list: C581608:EFTUD2 protein, human; D010445:Peptide Elongation Factors; D017415:Ribonucleoprotein, U5 Small Nuclear
keywords: EFTUD2; coloboma; microphthalmia; retinal dystrophy; zebrafish