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.

• Authors: Anneke T Vulto-van Silfhout, Tadashi Nakagawa, Nadia Bahi-Buisson, Stefan A Haas, Hao Hu, Melanie Bienek, Lisenka E L M Vissers, Christian Gilissen, Andreas Tzschach, Andreas Busche, Jörg Müsebeck, Patrick Rump, Inge B Mathijssen, Kristiina Avela, Mirja Somer, Fatma Doagu, Anju K Philips, Anita Rauch, Alessandra Baumer, Krysta Voesenek, Karine Poirier, Jacqueline Vigneron, Daniel Amram, Sylvie Odent, Magdalena Nawara, Ewa Obersztyn, Jacek Lenart, Agnieszka Charzewska, Nicolas Lebrun, Ute Fischer, Willy M Nillesen, Helger G Yntema, Irma Järvelä, Hans-Hilger Ropers, Bert B A de Vries, Han G Brunner, Hans van Bokhoven, F Lucy Raymond, Michèl A A P Willemsen, Jamel Chelly, Yue Xiong, A James Barkovich, Vera M Kalscheuer, Tjitske Kleefstra, Arjan P M de Brouwer
• Journal: Human mutation (Hum Mutat) Vol. 36 Issue 1 Pg. 106-17 (Jan 2015) ISSN: 1098-1004 [Electronic] United States
• PMID: 25385192 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY PERIODICALS, INC.

Chemical References

• CUL4B protein, human
• Cell Cycle Proteins
• Cullin Proteins
• Nerve Tissue Proteins
• WDR62 protein, human

Topics

• Adolescent
• Adult
• Brain (pathology)
• Cell Cycle Proteins
• Cells, Cultured
• Child
• Child, Preschool
• Cullin Proteins (genetics, metabolism)
• Genetic Association Studies
• HEK293 Cells
• Humans
• Infant
• Male
• Malformations of Cortical Development (genetics, metabolism, pathology)
• Mental Retardation, X-Linked (genetics, metabolism, pathology)
• Middle Aged
• Nerve Tissue Proteins (metabolism)
• Pedigree
• Sequence Analysis, DNA
• Young Adult