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Ubiquitination plays a crucial role in neurodevelopment as exemplified by Angelman syndrome, which is caused by genetic alterations of the ubiquitin ligase-encoding UBE3A gene. Although the function of UBE3A has been widely studied, little is known about its paralog UBE3B. By using exome and capillary sequencing, we here identify biallelic UBE3B mutations in four patients from three unrelated families presenting an autosomal-recessive blepharophimosis-ptosis-intellectual-disability syndrome characterized by developmental delay, growth retardation with a small head circumference, facial dysmorphisms, and low cholesterol levels. UBE3B encodes an uncharacterized E3 ubiquitin ligase. The identified UBE3B variants include one frameshift and two splice-site mutations as well as a missense substitution affecting the highly conserved HECT domain. Disruption of mouse Ube3b leads to reduced viability and recapitulates key aspects of the human disorder, such as reduced weight and brain size and a downregulation of cholesterol synthesis. We establish that the probable Caenorhabditis elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions. Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals.
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PMID:Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. 2320 Aug 64

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis-intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new" syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome".
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PMID:Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations. 2461 90

Recent genome-wide studies found that patients with hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels suffer from Kaufman oculocerebrofacial syndrome (KOS, also reported as blepharophimosis-ptosis-intellectual disability syndrome). The primary cause of KOS is autosomal recessive mutations in the gene UBE3B However, to date, there are no studies that have determined the cellular or enzymatic function of UBE3B. Here, we report that UBE3B is a mitochondrion-associated protein with homologous to the E6-AP Cterminus (HECT) E3 ubiquitin ligase activity. Mutating the catalytic cysteine (C1036A) or deleting the entire HECT domain (amino acids 758-1068) results in loss of UBE3B's ubiquitylation activity. Knockdown of UBE3B in human cells induces changes in mitochondrial morphology and physiology, a decrease in mitochondrial volume, and a severe suppression of cellular proliferation. We also discovered that UBE3B interacts with calmodulin via its N-terminal isoleucine-glutamine (IQ) motif. Deletion of the IQ motif (amino acids 29-58) results in loss of calmodulin binding and a significant increase in the in vitro ubiquitylation activity of UBE3B. In addition, we found that changes in calcium levels in vitro disrupt the calmodulin-UBE3B interaction. These studies demonstrate that UBE3B is an E3 ubiquitin ligase and reveal that the enzyme is regulated by calmodulin. Furthermore, the modulation of UBE3B via calmodulin and calcium implicates a role for calcium signaling in mitochondrial protein ubiquitylation, protein turnover, and disease.
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PMID:UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase. 2800 68

Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.
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PMID:Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails. 2800 43

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder caused by biallelic variants in UBE3B. Kaufman oculocerebrofacial syndrome is characterized by a recognizable pattern of malformations including moderate to severe intellectual disability, growth deficiency, microcephaly and a distinctive facial gestalt. Common craniofacial features include short upslanting palpebral fissures, blepharophimosis or ptosis, ear anomalies, hearing loss, palate anomalies and stridor/laryngomalacia. The aim of this study was to describe the phenotypic features and the genotype of five new individuals from three unrelated families, and to review systematically the published information of 26 cases. The main features are summarized contributing to further characterize the natural history of the disease. Novel phenotypic features and two novel pathogenic variants in UBE3B are reported: A splice site variant (c.2569-1G > C) and a nonsense variant (c.518C > A, p.Ser173Ter). Kaufman oculocerebrofacial syndrome is likely an underdiagnosed disorder which can be clinically recognized based on its distinctive facial gestalt and relatively homogenous natural history.
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PMID:Further phenotypic characterization of Kaufman oculocerebrofacial syndrome: report of five new cases and literature review. 3116 49

Blepharophimosis-ptosis-intellectual disability syndrome (BPID) is an extremely rare recognizable blepharophimosis intellectual disability syndrome (BID). It is caused by biallelic variants in the UBE3B gene with only 24 patients described worldwide. Herein, we report on the clinical, brain imaging and molecular findings of additional nine patients from six unrelated Egyptian families. Patients presented with the characteristic features of the syndrome including blepharophimosis, ptosis, upslanted palpebral fissures with epicanthic folds, hypertelorism, long philtrum, high arched palate, micrognathia, microcephaly, and intellectual disability. Other findings were congenital heart disease (5 patients), talipes equinovarus (5 patients), genital anomalies (5 patients), autistic features (4 patients), cleft palate (2 patients), hearing loss (2 patients), and renal anomalies (1 patient). New or rarely reported findings were spherophakia, subvalvular aortic stenosis and hypoplastic nails, and terminal phalanges. Brain MRI, performed for 7 patients, showed hypogenesis or almost complete agenesis of corpus callosum. Genetic studies revealed five novel homozygous UBE3B variants. Of them, the c.1076G>A (p.W359*) was found in three patients from two unrelated families who shared similar haplotype suggesting a likely founder effect. Our results strengthen the clinical, dysmorphic, and brain imaging characteristic of this unique type of BID and extend the mutational spectrum associated with the disorder.
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PMID:Blepharophimosis-ptosis-intellectual disability syndrome: A report of nine Egyptian patients with further expansion of phenotypic and mutational spectrum. 3294 9