Variants in CUL4B are associated with cerebral malformations.
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.
Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
Anneke T
AT
Vulto-van Silfhout
Tadashi
T
Nakagawa
Nadia
N
Bahi-Buisson
Stefan A
SA
Haas
Hao
H
Hu
Melanie
M
Bienek
Lisenka E L M
LE
Vissers
Christian
C
Gilissen
Andreas
A
Tzschach
Andreas
A
Busche
Jörg
J
Müsebeck
Patrick
P
Rump
Inge B
IB
Mathijssen
Kristiina
K
Avela
Mirja
M
Somer
Fatma
F
Doagu
Anju K
AK
Philips
Anita
A
Rauch
Alessandra
A
Baumer
Krysta
K
Voesenek
Karine
K
Poirier
Jacqueline
J
Vigneron
Daniel
D
Amram
Sylvie
S
Odent
Magdalena
M
Nawara
Ewa
E
Obersztyn
Jacek
J
Lenart
Agnieszka
A
Charzewska
Nicolas
N
Lebrun
Ute
U
Fischer
Willy M
WM
Nillesen
Helger G
HG
Yntema
Irma
I
Järvelä
Hans-Hilger
HH
Ropers
Bert B A
BB
de Vries
Han G
HG
Brunner
Hans
H
van Bokhoven
F Lucy
FL
Raymond
Michèl A A P
MA
Willemsen
Jamel
J
Chelly
Yue
Y
Xiong
A James
AJ
Barkovich
Vera M
VM
Kalscheuer
Tjitske
T
Kleefstra
Arjan P M
AP
de Brouwer
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism*; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D055815:Young Adult
C517832:CUL4B protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D009419:Nerve Tissue Proteins; C552527:WDR62 protein, human
CUL4B; WDR62; cortical dysplasia; hydrocephalus; intellectual disability; mutation