Deletions of chromosome 1q42-q44 have been reported in a variety of developmental abnormalities of the brain, including microcephaly (MIC) and agenesis of the corpus callosum (ACC). Here, we describe detailed mapping studies of patients with unbalanced structural rearrangements of distal 1q4. These define a 3.5-Mb critical region extending from RP11-80B9 to RP11-241M7 that we hypothesize contains one or more genes that lead to MIC and ACC when present in only one functional copy. Next, mapping of a balanced reciprocal t(1;13)(q44;q32) translocation in a patient with postnatal MIC and ACC demonstrated a breakpoint within this region that is situated 20 kb upstream of AKT3, a serine-threonine kinase. The murine orthologue Akt3 is required for the developmental regulation of normal brain size and callosal development. Whereas sequencing of AKT3 in a panel of 45 patients with ACC did not demonstrate any pathogenic variations, whole-mount in situ hybridization confirmed expression of Akt3 in the developing central nervous system during mouse embryogenesis. AKT3 represents an excellent candidate for developmental human MIC and ACC, and we suggest that haploinsufficiency causes both postnatal MIC and ACC.
Bibliographical noteFunding Information:
E.B. was funded by the Health Foundation. G.B. is a Wellcome Trust Senior Clinical Research Fellow. We thank the staff of the Northwest Regional Cytogenetic Department, St Mary’s Hospital, Manchester, and Northern Ireland Regional Cytogenetic Laboratory, Belfast City Hospital, for initial karyotyping of patients. We thank the staff of the DNA Sequencing Facility of the University of Chicago Cancer Research Center and the Sanger Centre Clone Supply Unit for providing BAC and fosmid clones. We also thank the staff and students of the Millen and Dobyns Labs at the University of Chicago for much advice and assistance. This work was supported in part by grants from the National Institutes of Health (NIH) to E.H.S. and to W.B.D. and K.J.M. (R01-NS050375) and from the March of Dimes. This publication was made possible in part by grant UL RR024131-01 from the National Center for Research Resources (NCRR) (a component of the NIH) and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or the NIH.