Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum.

ABSTRACT

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.