Variants in<i>CUL4B</i>are Associated with Cerebral Malformations

Silfhout, Anneke T. Vulto-van; Nakagawa, Tadashi; Bahi‐Buisson, Nadia; Haas, Stefan A.; Hu, Hao; Bienek, Melanie; Vissers, Lisenka E.L.M.; Gilissen, Christian; Tzschach, Andreas; Busche, Andreas; Müsebeck, Jörg; Rump, Patrick; Mathijssen, Inge B.; Avela, Kristiina; Somer, Mirja; Doagu, Fatma; Philips, Anju K; Rauch, Anita; Baumer, Alessandra; Voesenek, Krysta; Poirier, Karine; Vigneron, Jacqueline; Amram, Daniel; Odent, Sylvie; Nawara, Magdalena; Obersztyn, Ewa; Lenart, Jacek; Charzewska, Agnieszka; Lebrun, Nicolas; Fischer, Ute; Nillesen, Willy M.; Yntema, Helger G.; Järvelä, Irma; Ropers, Hans Hilger; Vries, Bert B.A. de; Brunner, Han G.; Bokhoven, Hans van; Raymond, F. Lucy; Willemsen, M.A.A.P.; Chelly, Jamel; Xiong, Yue; Barkovich, A. James; Kalscheuer, Vera M.; Kleefstra, Tjitske; Brouwer, Arjan P.M. de

doi:10.1002/humu.22718

Cited by 38 publications

(53 citation statements)

References 48 publications

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“…Its dysregulation leads to various movement disturbances, dementia and hypogonadotropic hypogonadism [44,45]. Thus, it is not surprising that a growing group of ID proteins are directly involved in UPS-mediated protein degradation, such as UBE3A [46] [47], UBE2A [48,49,50,51], UBE3B [52,47], HUWE1 [53,54,55], MID1 [56][57][58][59], CUL4B [60,[61][62][63], UBR1 [64,65,66], TRIP12 [67][68][69], and RNF216 [45,[70][71][72].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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“…Other reports have identified truncations, aberrant splicing and deletions in CUL4B in XLID patients presenting similar clinical features to those previously described (Badura-Stronka et al, 2010; Isidor et al, 2010; Londin et al, 2014; Zou et al, 2007). Recently, 9 novel mutations in CUL4B were identified and several CUL4B -associated cerebral defects were reported including: malformations of cortical development, ventriculomegaly and diminished white matter volume (Vulto-van Silfhout et al, 2015). …”

Section: Clinical Relevancementioning

confidence: 99%

Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

Hannah

Zhou

2015

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The cullin 4 subfamily of genes includes CUL4A and CUL4B, which share a mostly identical amino acid sequence aside from the elongated N-terminal region in CUL4B. Both act as scaffolding proteins for modular cullin RING ligase 4 (CRL4) complexes which promote the ubiquitination of a variety of substrates. CRL4 function is vital to cells as loss of both genes or their shared substrate adaptor protein DDB1 halts proliferation and eventually leads to cell death. Due to their high structural similarity, CUL4A and CUL4B share a substantial overlap in function. However, in some cases, differences in subcellular localization, spatiotemporal expression patterns and stress-inducibility preclude functional compensation. In this review, we highlight the most essential functions of the CUL4 genes in: DNA repair and replication, chromatin-remodeling, cell cycle regulation, embryogenesis, hematopoiesis and spermatogenesis. CUL4 genes are also clinically relevant as dysregulation can contribute to the onset of cancer and CRL4 complexes are often hijacked by certain viruses to promote viral replication and survival. Also, mutations in CUL4B have been implicated in a subset of patients suffering from syndromic X-linked intellectual disability (AKA mental retardation). Interestingly, the antitumor effects of immunomodulatory drugs are caused by their binding to the CRL4CRBN complex and re-directing the E3 ligase towards the Ikaros transcription factors IKZF1 and IKZF3. Because of their influence over key cellular functions and relevance to human disease, CRL4s are considered promising targets for therapeutic intervention.

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“…Variants of this gene are a known cause of the Cabezas type of X-linked syndromic ID (MRXSC or Cabezas syndrome, MIM #300354). 4–6 A screening of XLID families and patients with ID using targeted panel-based next-generation sequencing (NGS) determined the frequency of CUL4B variants leading to XLID and ID, which were ~2% (8/407) 7 –3% (8/250) 4 and 0.5% (5/986) 8 –0.9% (1/106), 9 respectively. This result implicates CUL4B as one of the most commonly mutated genes with loss-of-function variants in patients with ID, regardless of their mode of inheritance.…”

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“…Patients with Cabezas syndrome display overlapping phenotypes, including short stature, hypogonadism, gait abnormalities and other variable features such as ID, seizures, tremors, behavioral problems, macrocephaly, obesity and various dysmorphic features. 7 The presence of these overlapping features other than ID are indicative of the syndrome associated with CUL4B variants, 7 and a guideline can be used to identify potential patients with this syndrome (Supplementary Table S1); 4 however, the only previously reported consistent feature in affected individuals was ID, 4 and at least some of these features are commonly observed among individuals with ID. 10 Indeed, some CUL4B -associated XLID cases with no features or partially overlapping features have been reported.…”

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confidence: 99%

“…Brain magnetic resonance imaging showed cortical dysplasia, ventriculomegaly, loss of cerebral white matter and a thin corpus callosum (Figure 1), which were reported to be observed in 33%, 53%, 27% and 20% of XLID cases with CUL4B mutations, respectively. 7 At 4 years of age, the patient visited a pediatric neurology department because of frequent complex partial seizures. Normal results were obtained from routine laboratory tests and metabolic surveys.…”

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Genome-first approach diagnosed Cabezas syndrome via novel CUL4B mutation detection

et al. 2017

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Cabezas syndrome is a syndromic form of X-linked intellectual disability primarily characterized by a short stature, hypogonadism and abnormal gait, with other variable features resulting from mutations in the CUL4B gene. Here, we report a clinically undiagnosed 5-year-old male with severe intellectual disability. A genome-first approach using targeted exome sequencing identified a novel nonsense mutation [NM_003588.3:c.2698G>T, p.(Glu900*)] in the last coding exon of CUL4B, thus diagnosing this patient with Cabezas syndrome.

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Variants inCUL4Bare Associated with Cerebral Malformations

Cited by 38 publications

References 48 publications

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

Genome-first approach diagnosed Cabezas syndrome via novel CUL4B mutation detection

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