RT Journal Article
SR Electronic
T1 Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 493
OP 499
DO 10.1136/jmedgenet-2012-101405
VO 50
IS 8
A1 Elisabetta Flex
A1 Andrea Ciolfi
A1 Viviana Caputo
A1 Valentina Fodale
A1 Chiara Leoni
A1 Daniela Melis
A1 Maria Francesca Bedeschi
A1 Laura Mazzanti
A1 Antonio Pizzuti
A1 Marco Tartaglia
A1 Giuseppe Zampino
YR 2013
UL http://jmg.bmj.com/content/50/8/493.abstract
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.