title: Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome.
abstract: BACKGROUND
  Kaufman oculocerebrofacial syndrome (KOS) is a developmental disorder characterised by reduced growth, microcephaly, ocular anomalies (microcornea, strabismus, myopia, and pale optic disk), distinctive facial features (narrow palpebral fissures, telecanthus, sparse and laterally broad eyebrows, preauricular tags, and micrognathia), mental retardation, and generalised hypotonia. KOS is a rare, possibly underestimated condition, with fewer than 10 cases reported to date. Here we investigate the molecular cause underlying KOS.
  
  
  METHODS
  An exome sequencing approach was used on a single affected individual of an Italian consanguineous family coupled with mutation scanning using Sanger sequencing on a second unrelated subject with clinical features fitting the disorder.
  
  
  RESULTS
  Exome sequencing was able to identify homozygosity for a novel truncating mutation (c.556C>T, p.Arg186stop) in UBE3B, which encodes a widely expressed HECT (homologous to the E6-AP carboxyl terminus) domain E3 ubiquitin-protein ligase. Homozygosity for a different nonsense lesion affecting the gene (c.1166G>A, p.Trp389stop) was documented in the second affected subject, supporting the recessive mode of inheritance of the disorder. Mutation scanning of the entire UBE3B coding sequence on a selected cohort of subjects with features overlapping, in part, those recurring in KOS did not reveal disease-causing mutations, suggesting phenotypic homogeneity of UBE3B lesions.
  
  
  CONCLUSIONS
  Our data provide evidence that KOS is caused by UBE3B loss of function, and further demonstrate the impact of misregulation of protein ubiquitination on development and growth. The available clinical records, including those referring to four UBE3B mutation-positive subjects recently described as belonging to a previously unreported entity, which fits KOS, document the clinical homogeneity of this disorder.
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superioredi Sanità, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciolfi
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.forename: Valentina
authors.initials: V
authors.lastname: Fodale
authors.forename: Chiara
authors.initials: C
authors.lastname: Leoni
authors.forename: Daniela
authors.initials: D
authors.lastname: Melis
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Bedeschi
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.forename: Antonio
authors.initials: A
authors.lastname: Pizzuti
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
mesh_terms: D001483:Base Sequence; D002648:Child; D059472:Exome; D005124:Eye Abnormalities / Q000201:enzymology* / Q000235:genetics*; D019066:Facies; D005260:Female; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology* / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000201:enzymology* / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C482647:UBE3B protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Clinical genetics; Developmental; Diagnosis; Genome-wide; Molecular genetics