Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture.
Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5-Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4,000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. Magnetic resonance imaging and postmortem brain analysis supports important roles for WDR62 in the proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest it has central roles in many aspects of cerebral cortical development.
Yu
Timothy W
TW
Division of Genetics, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts, USA.
Mochida
Ganeshwaran H
GH
Tischfield
David J
DJ
Sgaier
Sema K
SK
Flores-Sarnat
Laura
L
Sergi
Consolato M
CM
Topçu
Meral
M
McDonald
Marie T
MT
Barry
Brenda J
BJ
Felie
Jillian M
JM
Sunu
Christine
C
Dobyns
William B
WB
Folkerth
Rebecca D
RD
Barkovich
A James
AJ
Walsh
Christopher A
CA
D001921:Brain / Q000002:abnormalities / Q000033:anatomy & histology / Q000473:pathology; D018797:Cell Cycle Proteins; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D003241:Consanguinity; D004260:DNA Repair / Q000235:genetics; D005190:Family; D005260:Female; D006179:Gyrus Cinguli / Q000002:abnormalities* / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C552527:WDR62 protein, human