Mapping of Deletion and Translocation Breakpoints in 1q44 Implicates the Serine/threonine Kinase AKT3 in Postnatal Microcephaly and Agenesis of the Corpus Callosum

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2007 Aug 2

PMID 17668379

Citations 74

Authors

Elena Boland

Jill Clayton-Smith

Victoria G Woo

Shane McKee

Forbes D C Manson

Livija Medne

Elaine Zackai

Eric A Swanson

David Fitzpatrick

Kathleen J Millen

Elliott H Sherr

William B Dobyns

Graeme C M Black

Affiliations

Soon will be listed here.

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.

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References

Meinecke P, Vogtel D . A specific syndrome due to deletion of the distal long arm of chromosome 1. Am J Med Genet. 1987; 28(2):371-6. DOI: 10.1002/ajmg.1320280215. View

Cho H, Mu J, Kim J, Thorvaldsen J, Chu Q, Crenshaw 3rd E . Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001; 292(5522):1728-31. DOI: 10.1126/science.292.5522.1728. View

Chong S, Pack S, Roschke A, Tanigami A, Carrozzo R, Smith A . A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. Hum Mol Genet. 1997; 6(2):147-55. DOI: 10.1093/hmg/6.2.147. View

Daniel A, Baker E, Chia N, Haan E, Malafiej P, Hinton L . Recombinants of intrachromosomal transposition of subtelomeres in chromosomes 1 and 2: a cause of minute terminal chromosomal imbalances. Am J Med Genet A. 2003; 117A(1):57-64. DOI: 10.1002/ajmg.a.10048. View

Jordan T, Hanson I, Zaletayev D, Hodgson S, Prosser J, Seawright A . The human PAX6 gene is mutated in two patients with aniridia. Nat Genet. 1992; 1(5):328-32. DOI: 10.1038/ng0892-328. View

Mears A, Jordan T, Mirzayans F, Dubois S, Kume T, Parlee M . Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet. 1998; 63(5):1316-28. PMC: 1377542. DOI: 10.1086/302109. View

Hathout E, Thompson K, Baum M, DUMARS K . Association of terminal chromosome 1 deletion with sertoli cell-only syndrome. Am J Med Genet. 1998; 80(4):396-8. View

Fantes J, Ragge N, Lynch S, McGill N, Collin J, Howard-Peebles P . Mutations in SOX2 cause anophthalmia. Nat Genet. 2003; 33(4):461-3. DOI: 10.1038/ng1120. View

Puthuran M, Rowland-Hill C, Simpson J, Pairaudeau P, Mabbott J, Morris S . Chromosome 1q42 deletion and agenesis of the corpus callosum. Am J Med Genet A. 2005; 138(1):68-9. DOI: 10.1002/ajmg.a.30888. View

10.

Kleinjan D, Van Heyningen V . Position effect in human genetic disease. Hum Mol Genet. 1998; 7(10):1611-8. DOI: 10.1093/hmg/7.10.1611. View

11.

Gleeson J, Allen K, Fox J, Lamperti E, Berkovic S, Scheffer I . Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell. 1998; 92(1):63-72. DOI: 10.1016/s0092-8674(00)80899-5. View

12.

Grinberg I, Northrup H, Ardinger H, Prasad C, Dobyns W, Millen K . Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat Genet. 2004; 36(10):1053-5. DOI: 10.1038/ng1420. View

13.

Bellacosa A, Testa J, Moore R, Larue L . A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities. Cancer Biol Ther. 2004; 3(3):268-75. DOI: 10.4161/cbt.3.3.703. View

14.

De Rosa G, Pardeo M, Bria S, Caresta E, Vasta I, Zampino G . Isolated myocardial non-compaction in an infant with distal 4q trisomy and distal 1q monosomy. Eur J Pediatr. 2005; 164(4):255-6. DOI: 10.1007/s00431-005-1620-4. View

15.

WALLIS D, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A . Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet. 1999; 22(2):196-8. DOI: 10.1038/9718. View

16.

Easton R, Cho H, Roovers K, Shineman D, Mizrahi M, Forman M . Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol. 2005; 25(5):1869-78. PMC: 549378. DOI: 10.1128/MCB.25.5.1869-1878.2005. View

17.

Brodbeck D, Cron P, Hemmings B . A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem. 1999; 274(14):9133-6. DOI: 10.1074/jbc.274.14.9133. View

18.

Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, Dobyns W . Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature. 1993; 364(6439):717-21. DOI: 10.1038/364717a0. View

19.

Kang J, Liu H, Li Y, Li R . Cloning and Distribution of rRP58, A Novel Neuronal Gene. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002; 33(5):563-568. View

20.

Bejerano G, Pheasant M, Makunin I, Stephen S, Kent W, Mattick J . Ultraconserved elements in the human genome. Science. 2004; 304(5675):1321-5. DOI: 10.1126/science.1098119. View