The central goal of this Program Project application is to address the central mechanism of human structural brain defects (SBD), utilizing the unique strengths of the Principal Investigators and the new breakthroughs in genetics and modeling. This Program Project Grant Application is designed to advance biomedical knowledge and make a high impact on our understanding of the basis of SBDs across the evolutionary scale, with the purpose of advancing our ability to diagnose and treat disease. In our preliminary data, we have established: 1] A broad database consisting of over 1500 human families with structural brain defects, highly enriched for first cousin consanguinity with multiple affected members. 2] Extensive development of mouse lines with neural-specific expression of Cre-recombinase. 3] A broad array of tools to study gene requirements in zebrafish development. 4] A proven track record of utilization of these unique reagents to study mechanisms of disease. As a result of our preliminary data, we have formulated this Program Project Grant Application with a two-fold thrust: 1] By taking advantage of the technical revolution in DNA sequencing and genetic engineering, we will uncover new causes of disease in humans. 2] By comparing phenotypes across these unique systems, each with its own strength/weakness we will enhance our understanding of the basic mechanisms of SBD. Since all Principal Investigators in this Program Project Grant Application have evidence for considering cell polarity as central to the developmental mechanisms of SBD, each Project has a focus on investigating cell polarity within the spectrum of the proposed Aims. Two Cores will be essential to the Program Project Grant Application since they will carry out essential functions of the Program Project Grant Application and benefit each Project: 1] Next-generation Sequencing Core to uncover new genetic causes of SBDs in each species. 2] Bioinformatics Core will provide essential functions to provide experimental design and analytical services with one-on-one training and data management and custom computational solutions.
Specific Aims of the Program Project Grant Application are: 1] To uncover a host of new developmental causes of SBD from this unique human DNA resource, as well as from mutagenized mice and zebrafish. 2] To explore cell-type specificities of disease and pathogenic mechanisms of SBDs using mice and zebrafish models. 3] To utilize newly uncovered mice and zebrafish genes involved in SBDs for analysis in this human population. We believe that this Program Project Grant Application will have a major impact on our understanding of the cellular and molecular mechanisms that underlie a variety of SBDs, fully taking advantage of new breakthroughs in genomics technologies, which will set the stage for improved diagnosis and treatment.
This Program Project Grant Application is focused on understanding how the human brain develops and the genes that regulate its structural specificities. By utilizing inbred families, we will make maximal use of next-generation sequencing technologies, with the highest likelihood of uncovering mechanisms of development common across the evolutionary scale.
|Zaki, Maha S; Selim, Laila; El-Bassyouni, Hala T et al. (2016) Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients. Eur J Paediatr Neurol 20:714-22|
|Johansen, Anide; Rosti, Rasim O; Musaev, Damir et al. (2016) Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features. Am J Hum Genet 99:912-916|
|Scott, Eric M; Halees, Anason; Itan, Yuval et al. (2016) Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet 48:1071-6|
|Rosti, Rasim O; Dikoglu, Esra; Zaki, Maha S et al. (2016) Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene. Am J Med Genet A 170A:992-8|
|Jerber, Julie; Zaki, Maha S; Al-Aama, Jumana Y et al. (2016) Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. Am J Hum Genet 99:1181-1189|
|Li, Hongda; Saucedo-Cuevas, Laura; Regla-Nava, Jose A et al. (2016) Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation. Cell Stem Cell 19:593-598|
|Roosing, Susanne; Rosti, Rasim O; Rosti, Basak et al. (2016) Identification of a homozygous nonsense mutation in KIAA0556 in a consanguineous family displaying Joubert syndrome. Hum Genet 135:919-21|
|Li, Hongda; Bielas, Stephanie L; Zaki, Maha S et al. (2016) Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly. Am J Hum Genet 99:501-10|
|Breuss, Martin W; Sultan, Tipu; James, Kiely N et al. (2016) Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly. Am J Hum Genet 99:228-35|
|Kariminejad, A; SchÃ¶ls, L; SchÃ¼le, R et al. (2016) CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia. Eur J Paediatr Neurol 20:782-7|
Showing the most recent 10 out of 57 publications