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. 2013 Aug;50(8):493-9.
doi: 10.1136/jmedgenet-2012-101405. Epub 2013 May 17.

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

Elisabetta Flex  1 , Andrea Ciolfi, Viviana Caputo, Valentina Fodale, Chiara Leoni, Daniela Melis, Maria Francesca Bedeschi, Laura Mazzanti, Antonio Pizzuti, Marco Tartaglia, Giuseppe Zampino
Affiliations
Free PMC article

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

Elisabetta Flex et al. J Med Genet. 2013 Aug.
Free PMC article

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.

Keywords: Clinical genetics; Developmental; Diagnosis; Genome-wide; Molecular genetics.

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Figures

Figure 1
Figure 1
Craniofacial features in Kaufman oculocerebrofacial syndrome and UBE3B domain structure. (A) The recognisable facial gestalt of the two affected subjects (UCSC_KS01, above; UCSC_KS02, below). Note the distinctive facies of the two affected subjects with microcephaly, sparse eyebrows with unusual profile, upslanting and narrow palpebral fissures, strabismus, cup shaped ears, preauricular tags, and micrognathia. (B) Pedigree structure of family UCSC_KS01. Genotyped members are indicated. (C) Scheme of the UBE3B domain structure. The ubiquitin ligase comprises an N-terminal IQ domain (IQ), and a C-terminal catalytic domain (homologous to the E6-AP carboxyl terminus). Numbers below the diagram indicate the amino acid boundaries of those domains. The location of identified mutations in patients UCSC_KS01 and UCSC_KS02 is also reported.
Figure 2
Figure 2
Truncating and missense mutations in UBE3B cause Kaufman oculocerebrofacial syndrome. (A) Chromatograms documenting homozygosity for the nonsense mutations identified in the two affected individuals included in this study are reported together with the respective reference sequences. (B) Location of disease causative mutations. The UBE3B gene includes 26 coding exons. The 5′- and 3′-untranslated regions are shown in black. Exonic regions coding for the IQ motif and the HECT domain are reported in blue and orange, respectively. The mutations identified in the present study are shown above the diagram, while those reported by Basel-Vanagaite et al are listed below. Homozygosity was documented in four unrelated subjects (black), while compound heterozygosity was reported in two siblings (red).
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References

    1. Kaufman R, Rimoin DL, Prensky AL, Sly WS. An oculocerebrofacial syndrome. Birth Defects Orig Art Ser 1971;7:135–8 - PubMed
    1. Jurenka SB, Evans J. Kaufman oculocerebrofacial syndrome: case report. Am J Med Genet 1979;3:15–19 - PubMed
    1. Garcia-Cruz D, Arreola R, Sanchez-Corona J, Garcia-Cruz O, Renteria R, Villar V, Gonzalez ME, Vargas-Moyeda E, Cantu JM. Kaufman oculocerebrofacial syndrome: a corroborative report. Dysmorph Clin Genet 1988;1:152–4
    1. Figuera LE, Garcia-Cruz D, Ramirez-Duenas ML, Rivera-Robles V, Cantu JM. Kaufman oculocerebrofacial syndrome: report of two new cases and further delineation. Clin Genet 1993;44:98–101 - PubMed
    1. Verloes A, Bremond-Grignac D, Isidor B, David A, Baumann C, Leroy MA, Stevens R, Gillerot Y, Heron D, Heron B, Benzacken B, Lacombe D, Brunner H, Bitoun P. Blepharophimosis-mental retardation (BMR) syndromes: a proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one X-linked and one autosomal recessive. Am J Med Genet A 2006;140:1285–96 - PubMed

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