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Original article
Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome
  1. Elisabetta Flex1,
  2. Andrea Ciolfi1,2,
  3. Viviana Caputo3,
  4. Valentina Fodale1,
  5. Chiara Leoni4,
  6. Daniela Melis5,
  7. Maria Francesca Bedeschi6,
  8. Laura Mazzanti7,
  9. Antonio Pizzuti3,
  10. Marco Tartaglia1,
  11. Giuseppe Zampino4
  1. 1Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy
  2. 2Dipartimento di Medicina Molecolare, Università “La Sapienza”, Rome, Italy
  3. 3Dipartimento di Medicina Sperimentale, Università “La Sapienza”, Rome, Italy
  4. 4Dipartimento di Scienze Pediatriche, Università Cattolica del Sacro Cuore, Rome, Italy
  5. 5Dipartimento di Pediatria, Facoltà di Medicina e Chirurgia, Università “Federico II”, Naples, Italy
  6. 6UOD Genetica Medica, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
  7. 7Dipartimento di Pediatria, Università degli Studi di Bologna, Bologna, Italy
  1. Correspondence to Dr Marco Tartaglia, Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome 00161, Italy; mtartaglia{at}


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.

Discussion 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.

  • Clinical genetics
  • Developmental
  • Diagnosis
  • Genome-wide
  • Molecular genetics

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