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Variants in CUL4B are associated with cerebral malformations.

ABSTRACT: Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.

SUBMITTER: Vulto-van Silfhout AT

PROVIDER: S-EPMC4608231 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Variants in CUL4B are associated with cerebral malformations.

Vulto-van Silfhout Anneke T AT Nakagawa Tadashi T Bahi-Buisson Nadia N Haas Stefan A SA Hu Hao H Bienek Melanie M Vissers Lisenka E L M LE Gilissen Christian C Tzschach Andreas A Busche Andreas A Müsebeck Jörg J Rump Patrick P Mathijssen Inge B IB Avela Kristiina K Somer Mirja M Doagu Fatma F Philips Anju K AK Rauch Anita A Baumer Alessandra A Voesenek Krysta K Poirier Karine K Vigneron Jacqueline J Amram Daniel D Odent Sylvie S Nawara Magdalena M Obersztyn Ewa E Lenart Jacek J Charzewska Agnieszka A Lebrun Nicolas N Fischer Ute U Nillesen Willy M WM Yntema Helger G HG Järvelä Irma I Ropers Hans-Hilger HH de Vries Bert B A BB Brunner Han G HG van Bokhoven Hans H Raymond F Lucy FL Willemsen Michèl A A P MA Chelly Jamel J Xiong Yue Y Barkovich A James AJ Kalscheuer Vera M VM Kleefstra Tjitske T de Brouwer Arjan P M AP

Human mutation 20150101 1

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventricu ...[more]

PMID: 25385192

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Project description:BackgroundCerebral cavernous malformations (CCMs) are vascular anomalies of the nervous system mostly located in the brain presenting sporadically or familial. Causes of familial forms are mutations in CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10) genes. Sporadic forms with no affected relative most often have only one lesion and no germ line mutations. However, a number of sporadic cases with multiple lesions have been reported and are indeed genetic cases with a de novo mutation or a mutation inherited from an asymptomatic parent.MethodsHere, we performed an analysis of regulatory region of CCM genes in 60 sporadic patients, negative for mutations in coding region and intron-exon boundaries and large deletion/duplications in CCM genes by direct sequencing and MLPA. Among 5 variants identified in 851-bp region shared by CCM3 and SERPINI1 genes and acting as asymmetric bidirectional promoter, two polymorphisms c.-639 T > C/rs9853967 and c.-591 T > C/rs11714980 were selected. A case-control study was performed to analyze their possible relationships with sporadic CCMs. Promoter haplotypes activities on CCM3/SERPINI1 genes expression were tested by dual-luciferase assay.ResultsNo variants were identified in CCM1 and CCM2 regulatory regions. In CCM3/SERPINI1 asymmetric bidirectional promoter 5 variants, 2 of them unknown and 3 corresponding to polymorphisms c.-639 T > C/rs9853967, c.-591 T > C/rs11714980 and c.-359G > A/rs9834676 were detected. While rs9853967 and rs11714980 polymorphisms fall in a critical regulatory fragment outside the minimal promoter in intergenic region, other variants had no effects on transcription factor binding according to RegRNA tool. Case-control study performed on 60 patients and 350 healthy controls showed frequencies of the mutated alleles significantly higher in the control group than in patients. Furthermore, the functional assay showed a significant reduction of CCM3 expression for C-C haplotype even more than for T-C and C-T haplotypes. In SERPINI1 direction, the reduction was not statistically significant.ConclusionsOur data indicated that rs9853967 and rs11714980 polymorphisms could be associated with a protective role in CCM disease.

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Variants in CUL4B are associated with cerebral malformations.

Publications

Variants in CUL4B are associated with cerebral malformations.

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