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Recessive LAMC3 mutations cause malformations of occipital cortical development

Abstract

The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin γ3 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations.

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Figure 1: LAMC3 mutation in NG 49 with occipital cortical malformation.
Figure 2: Additional LAMC3 mutations in individuals with occipital cortical malformation.
Figure 3: Species differences in expression of LAMC3 in the cerebral cortex.
Figure 4: Temporal and spatial LAMC3 expression pattern.

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Acknowledgements

We are indebted to the subjects and families who have contributed to this study. We would like to thank M. State and J. Noonan for critical comments regarding the study and C. Camputaro for her help with the imaging studies. We acknowledge the use of Yale University Biomedical High Performance Computing Center for data analysis and storage. This study was supported by the Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics, and US National Institutes of Health grants RC2NS070477 (to M.G.), UL1RR024139NIH (Yale Clinical and Translational Science Award) and UO1MH081896 (to N.S.). SNP genotyping was supported in part by a US National Institutes of Health Neuroscience Microarray Consortium award U24 NS051869-02S1 (to S.M.).

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Authors and Affiliations

Authors

Contributions

M.G. designed the study, and T.B., K.Y.K., A.L., R.P.L., N.S., K.B. and M.G. designed the experiments. T.B., K.Y.K., A.L., K.B., S.Y., M.B., A.O.C., A.K.O. and S.M. performed the experiments. V.D., S.S., B.T., H.K. and C.Y. identified, consented and recruited the study subjects and provided clinical information. A.D. and R.A.B. performed and evaluated magnetic resonance imaging. T.O., H.B., K.D. and E.A. performed and evaluated three-dimensional cortical reconstruction and functional imaging studies. M.C. and R.P.L. developed the bioinformatics scripts for data analysis. W.J.B. provided critical reagents. T.B., T.O., K.Y., K.B., R.P.L. and M.G. analyzed the genetics data. K.Y.K., A.L., Y.Z., N.S. and M.G. analyzed the expression data. T.B., K.Y.K., A.L., R.P.L., N.S., K.B. and M.G. wrote the paper.

Corresponding author

Correspondence to Murat Günel.

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The authors have a provisional patent application under consideration based on the findings of this work.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–7 and Supplementary Figures 1–8. (PDF 1557 kb)

Supplementary Video 1

T2 axial MR images of patient NG 49-1 (MOV 2083 kb)

Supplementary Video 2

T2 sagittal MR images of patient NG 49-1 (MOV 2295 kb)

Supplementary Video 3

Audiovisual EEG monitoring of patient NG 367-1 (MOV 5256 kb)

Supplementary Video 4

T2 axial MR images of patient NG 367-1 (MOV 1410 kb)

Supplementary Video 5

T2 sagittal MR images of patient NG 367-1 (MOV 2570 kb)

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Barak, T., Kwan, K., Louvi, A. et al. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat Genet 43, 590–594 (2011). https://doi.org/10.1038/ng.836

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