Loss of function of the E3 ubiquitin-protein ligase UBE3B causes kaufman oculocerebrofacial syndrome

Elisabetta Flex, Andrea Ciolfi, Viviana Caputo, Valentina Fodale, Chiara Leoni, Daniela Melis, Maria Francesca Bedeschi, Laura Mazzanti, Antonio Pizzuti, Marco Tartaglia, Giuseppe Zampino

Research output: Contribution to journalArticle

19 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)493-499
Number of pages7
JournalJournal of Medical Genetics
Volume50
Issue number8
DOIs
Publication statusPublished - 2013

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Ubiquitin-Protein Ligases
Mutation
Exome
Micrognathism
Eyebrows
Microcephaly
Muscle Hypotonia
Ubiquitination
Strabismus
Optic Disk
Myopia
Eyelids
Growth and Development
Intellectual Disability
Kaufman oculocerebrofacial syndrome
Growth
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Loss of function of the E3 ubiquitin-protein ligase UBE3B causes kaufman oculocerebrofacial syndrome. / Flex, Elisabetta; Ciolfi, Andrea; Caputo, Viviana; Fodale, Valentina; Leoni, Chiara; Melis, Daniela; Bedeschi, Maria Francesca; Mazzanti, Laura; Pizzuti, Antonio; Tartaglia, Marco; Zampino, Giuseppe.

In: Journal of Medical Genetics, Vol. 50, No. 8, 2013, p. 493-499.

Research output: Contribution to journalArticle

Flex, E, Ciolfi, A, Caputo, V, Fodale, V, Leoni, C, Melis, D, Bedeschi, MF, Mazzanti, L, Pizzuti, A, Tartaglia, M & Zampino, G 2013, 'Loss of function of the E3 ubiquitin-protein ligase UBE3B causes kaufman oculocerebrofacial syndrome', Journal of Medical Genetics, vol. 50, no. 8, pp. 493-499. https://doi.org/10.1136/jmedgenet-2012-101405
Flex, Elisabetta ; Ciolfi, Andrea ; Caputo, Viviana ; Fodale, Valentina ; Leoni, Chiara ; Melis, Daniela ; Bedeschi, Maria Francesca ; Mazzanti, Laura ; Pizzuti, Antonio ; Tartaglia, Marco ; Zampino, Giuseppe. / Loss of function of the E3 ubiquitin-protein ligase UBE3B causes kaufman oculocerebrofacial syndrome. In: Journal of Medical Genetics. 2013 ; Vol. 50, No. 8. pp. 493-499.
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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. 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.",
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AU - Flex, Elisabetta

AU - Ciolfi, Andrea

AU - Caputo, Viviana

AU - Fodale, Valentina

AU - Leoni, Chiara

AU - Melis, Daniela

AU - Bedeschi, Maria Francesca

AU - Mazzanti, Laura

AU - Pizzuti, Antonio

AU - Tartaglia, Marco

AU - Zampino, Giuseppe

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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