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.

Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination

“…4,6,7,9,11,18 After chromosomal microarray testing has been available for the identification of submicroscopic chromosomal aberrations, many patients with submicroscopic deletions of 1q44 have been identified. 8,10,12,14,15 Now, precise genotype-phenotype correlation has been evaluated through the accumulation of patients with variable deletion sizes, and a minimal essential region has been proposed for expressing the main characteristics of 1q44 deletion syndrome.…”

“…8,10,12,14,15 Now, precise genotype-phenotype correlation has been evaluated through the accumulation of patients with variable deletion sizes, and a minimal essential region has been proposed for expressing the main characteristics of 1q44 deletion syndrome. 7,8,[14][15][16] Ballif et al 17 evaluated 22 patients with small interstitial deletions of 1q44 and demonstrated critical regions for microcephaly, ACC and seizures. Consequently, AKT3 was reported to be the gene responsible for microcephaly; zinc finger protein 238 gene (ZNF238) for ACC; and heterogeneous nuclear ribonucleoprotein U gene (HNRNPU) for seizures 17 ( Figure 5).…”

“…3 Several studies have investigated the critical region for 1q44 subtelomeric deletion syndrome and found that the core phenotypic features of 1q44 subtelomeric deletion syndrome are microcephaly, abnormalities of the corpus callosum (ACC) and seizures. [4][5][6][7][8][9][10][11][12][13][14][15][16] Recently, Ballif et al 17 analyzed patients with microdeletions of 1q44 and proposed certain genes that may be responsible for individual features.…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…These studies suggest that selective inhibition of AKT1 may be an effective therapy for cancer. However, in the postnatal brain, AKT3 appears to be the critical isoform, as deletion in mice results in decreased brain size (Easton et al, 2005), whereas in humans, haploinsufficiency of AKT3 has been associated with postnatal microcephaly (Boland et al, 2007). It remains unclear, which AKT isoform is the critical effector downstream of deregulated PI3K signaling in brain tumors.…”

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

“…Interestingly, deletion of the distal end of human chromosome-1q is linked to microcephaly with agenesis of the corpus callosum (e.g. [9][10][11], and a critical region contains only a handful of genes, including RP58. 9-12 RP58, also known as ZNF238, 13 encodes a transcription factor with a BTB/POZ and four zincfinger domains 14 that is highly conserved (495%) between humans and mice, suggesting conserved functions.…”