We have studied the genetics of hereditary diseases for the last 15 years. Currently we apply advanced next-generation sequencing (NGS) methodologies i.e. whole human genome sequencing, exome sequencing and sequencing of specific targeted disease-implicated genomic regions. These technologies, in combination with advanced bioinformatic data interpretation, have increased dramatically the identification probability of causal variants for genetic disorders. In collaboration with Sheba Medical Center and Duke University we have a collection of nearly 80 rare Mendelian diseases that have gone undeciphered for many years. Four diseases already deciphered in terms of specific genes and mutations are severe microcephally (asparagine synthetase, ASNS) Hereditary Spastic Paraplegia (tectonin beta-propeller repeat containing 2, (TECPR2) (Fig. 1), intractable diarrhea of infancy (IDIS) for which we discovered a regulatory region, enhancer, that is homozygously deleted in all patients.
Figure 1: Studies of genetic diseases using whole exome sequencing
A. A novel frame-shifting mutation discovered in four unrelated Jewish Bukharian HPS patients, leading to premature stop-codon in the gene TECPR2. B. The mutation decreases the protein levels of SQSTM1 (p62) and MAP1LC3B (LC3), two key autophagic proteins. The figure shows a summary of three immunoblotting replicates with anti-p62 antibody and anti-LC3 antibody for skin fibroblasts lysates of both affected and control. Basal - rich medium; str - starvation; baf - with the lysosomal inhibitor bafilomycin A. In collaboration with Z. Elazar and A. Gelman, Dept Biol Chemistry.
This genomic interval is still under studies both in a mouse model and in intestine cells in culture. For the Capillary Leak Syndrome (CLS), causing life threatening attacks of plasma leakage through the capillaries wall, we have identified a novel variant that heterozygously disrupts an essential base at a splice site in the cytoskeletal gene TLN1, introducing both exon skipping and intron retention. The Talin 1 gene (TLN1) participates in cell adhesion mechanism. Functional studies for the involvement of the mutation in the Capillary Leak Syndrome are ongoing. The polygenic/common/complex diseases under study are schizophrenia, in collaboration with Hadassah Medical Center and a skin disease – pemphigus vulgaris – in collaboration with Sourasky/Ichilov Medical Center.
- Ruzzo, E.K., Ben-Zeev, B., Hitomi, Y., Silver, D.L., Pelak, K., Dickson, S.P., Reznik-Wolf, H., Bar-Joseph, I., Oz-Levi, D., Lev, D., Lerman-Sagie, T., Leshinsky-Silver, E., Anikster, Y., Ben-Asher, E., Olender, T., Ge, D., Shianna, K.V., Lancet, D., Pras, E. and Goldstein, D.B. Exome-sequencing identifies a mutation in the ASNS gene as a cause of progressive microcephaly and brain atrophy in Iranian Jews (submitted).
- Oz-Levi D, Ben-Zeev B, Ruzzo EK, Hitomi Y, Gelman A, Pelak K, Anikster Y, Reznik-Wolf H, Bar-Joseph I, Olender T, Alkelai A, Weiss M, Ben-Asher E, Ge D, Shianna KV, Elazar Z, Goldstein DB, Pras E, Lancet D. Mutation in TECPR2 Reveals a Role for Autophagy in Hereditary Spastic Paraparesis. Am J Hum Genet. 2012 Dec 7;91(6):1065-72. doi: 10.1016/j.ajhg.2012.09.015.
• Fechete, R., Heinzel, A., Perco, P., Mönks, K., Söllner, J., Stelzer, G., Eder, S., Lancet, D., Oberbauer, R., Mayer, G. and Mayer, B. Mapping of molecular pathways, biomarkers and drug targets for diabetic nephropathy. Proteomics Clin Appl. (2011) Jun;5(5-6):354-66. doi: 10.1002/prca.201000136. Epub 2011 Apr 14.
• Alkelai, A., Ben- Asher E., Lancet, D., Macciardi, F. And Lerer, B. Identification of New Schizophrenia Susceptibility Loci in an Ethnically Homogeneous, Family-Based, Arab Israeli Sample. FASEB J 25(11):4011-4023 (2011).
• Slonimsky, A., Levy, I., Kohn, Y., Rigbi, A., Ben-Asher, E., Lancet, D. and Agam, G. Lymphoblast and brain expression of AHI1 and the novel primate specific gene, C6orf217, in schizophrenia and bipolar disorder. Schizophr res. 120, (1-3):159-166 (2010).
• Alkelai, A., Kohn, Y., Kanyas, K., Rigbi, A., Hamdan, A. Ben-Asher, E., Lancet, D. & Lerer, B. Evidence for an Interaction of Schizophrenia Susceptibility Loci on Chromosome 6q23.3 and 10q24.33-q26.13 in Arab Israeli Families. American J. Med. Genet. 150B(7):914-25 (2009).
• Grossman, I., Avidan, N., Singer. C., Goldstaub, D., Hayardeny, L., Eyal, E., Ben-Asher, E., Paperna, T., Lancet, D., Beckmann, J.S. and Miller, A. Pharmacogenetics of Glatiramer Acetate therapy for Multiple Sclerosis reveals drug-response markers. Pharmacogenetics and Genomics 17:657–666 (2007).
• Amann-Zalcenstein D, Avidan N, Kanyas K, Ebstein RP, Kohn Y, Hamdan A, Ben-Asher E, Karni O, Mujaheed M, Segman RH, Maier W, Macciardi F, Beckmann JS, Lancet D, Lerer B. AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to Schizophrenia. Eur J Hum Genet. (10):1111-9. ( 2006 )
• Amann D, Avidan N, Kanyas K, Kohn Y, Hamdan A, Ben-Asher E, Macciardi F, Beckmann JS, Lancet D, Lerer B. The trace amine receptor 4 gene is not associated with schizophrenia in a sample linked to chromosome 6q23. Mol Psychiatry. 11(2):119-21 (2006).
• Cohen-Gihon, I.; Lancet, D. and Yanai, I. Modular genes with metazoan specific domains have increased tissue specificity. Trends Genet. 21(4):210-3 (2005).
• Sharma, A., Sharma, V.K., Horn-Saban, S., Lancet, D., Ramachandran, S. and Brahmachari, S. Assessing natural variations in gene expression in humans by comparing with monozygotic twins. Physiol Genomics 21(1):117-23 (2005 )
• Kopelman, N, Lancet, D. and Yanai, I. Alternative splicing and gene duplication are inversely correlated evolutionary mechanisms. Nature Genet. 37(6):588-9 (2005).
• Starinsky, S., Figer, A., Ben-Asher, E., Geva, R., Flex, D., Fidder, H.H., Zidan, J., Lancet, D. and Friedman, E. Genotype phenotype correlations in Israeli colorectal cancer patients. . Int J Cancer. 114(1):58-73 (2005).
• Aloni, R. and Lancet, D. Conservation anchors in the vertebrate genome. Genome Biol. 6(7):115 (2005).
• Grossman, I., Avidan, N., Singer, C., Paperna, T., Lancet, D., Beckmann, J.S. and Miller, A. Genomic profiling of interpopulation diversdity guides prioritization of candidate-genes for autoimmunity. Genes and Immunity 5(6): 493-504 (2004).
• Adato, A., Vreugde, S., Joensuu, T., Avidan, N., Hamalainen, R., Belenkiy, O., Olander, Z., Bonne-Tamir, B., Ben-Asher, E., Espinos, C., Lehesjoki, A.-E., Flannery, J.G., Avraham, K.B., Pietrokovski, Sh., Sankila, E.-M., Beckmann, J.S. and Lancet, D.
USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses. European Journal of Human Genetics, 10: 339-350 (2002).
• Kirstein-Grossman, I., Beckmann, J.S., Lancet, D. and Miller, A. Pharmacogenetic Development of Personalized Medicine: Multiple Sclerosis Treatment as a Model. Drug News Perspect, 15(9): 558-567 (2002).
• Lahat, H., Pras, E., Olender, T., Avidan, N., Ben-Asher, E., Man, O., Levy-Nissrnbaum, E., Khoury, A., Lorber, A., Goldman, B., Lancet, D. and Eldar, M. A Missense Mutation in a Highly Conserved Region of CASQ2 is Associated with Autosomal Recessive Catecholamine Induced Polymorphic Ventricular Tachycardia in Bedouin Families in Israel. American Journal of Human Genetics, 69:1378-1384 (2001).
• Lander, E. et al., International Human Genome Sequencing Consortium, including Lancet, D. Initial sequencing and analysis of the human genome. Nature, 409:860-921 (2001).
• Bargal, R., Avidan, N., Ben-Asher, E., Olender, Z., Zeigler, M., Frumkin, A., Raas-Rothschild, A., Glusman, G., Lancet, D. and Bach, G. Identification of the gene causing Mucolipidosis type IV. Nature Genetics, 26(1): 120-123 (2000).