Characterization of Alternative Predisposition Loci for Schwannomatosis in SMARCB1/LZTR1-Negative Cases
Abstract
Schwannomatosis is a late-onset tumor predisposition disorder, one of the three major forms of neurofibromatosis. The key signs of this genetic disorder are multiple tumors referred to as schwannomas. The tumors originate from the Schwann cells, which form a nerve sheath, a natural insulator for peripheral nerves. A typical manifestation of schwannomatosis is severe chronic pain, which is often incapacitating and hardly bearable for the patients. So far, the majority of the patients have to live without a confirmed molecular diagnosis as only in about 30% of schwannomatosis cases constitutional mutations in either of two genes, SMARCB1 or LZTR1 on chromosome 22, can be identified. Without known molecular cause in the majority of cases, the hope for the development of pharmacological treatments is marginal, which is pertinent as only some of the schwannomas can be surgically removed without neurological consequences. Typically in the SMARCB1/LZTR1 positive cases, the following molecular signature is observed in every schwannoma: besides the "constitutional" SMARCB1/LZTR1 mutation, a somatic, i.e., tumor-specific, (partial) loss of chromosome 22q is present, as well as a different somatic NF2 mutation in every schwannoma. Patients with tumors that show these molecular signature of (partial) loss of chromosome 22q, as well as a different somatic NF2 mutation in every schwannoma, are called 22q-related cases. Some tumors from schwannomatosis patients with the somatic (partial) loss of 22q and a different NF2 mutation, however, do not show SMARCB1 or LZTR1 mutations. This suggests that in a portion of cases another predisposing genetic factor may still be located on chromosome 22. Furthermore, some patients develop multiple schwannomas, yet their tumors do not show somatic (partial) loss of 22q, neither NF2 mutations. In these patients, genetic predisposition is likely related to a different chromosome. Hence, taking all evidence together, other genetic factors predisposing to schwannomatosis likely exist either on chromosome 22 or elsewhere in the genome. In the proposed project, we intend to address genetic predisposistion to schwannomatosis in so far uncharacterized cases using a set of complementary genetic and biochemical approaches. First, in chromosome 22q-related cases, we will sequence carefully selected segments of chromomosome 22. Based on results of prior studies, preliminary data, and evolutionary conservation, these selected segments are most likely to be affected by mutations predisposing to schwannomatosis. Second, we will deregulate the expression of SMARCB1 and LZTR1 by silencing or overexpression of these genes in laboratory cultures of Schwann cells and their precursors. This means that we will respectively artificially induce or switch off production of proteins that are encoded by SMARCB1 and LZTR1. Silencing and overexpression are expected to cause qualitative and quantitative alterations in other genes, some of which may be functionally related to SMARCB1 and LZTR1 or act within the same pathway and/or complex. This way we will gain insight into functional associations of SMARCB1 and LZTR1 in Schwann cells and their precursors. Unraveling functional networks may help to delineate candidate diagnostic or therapeutic targets for subsequent studies, particularly in schwannomatosis cases that are not related to chromosome 22. Completion of these goals will have direct consequences for clinical molecular diagnostics as detection of mutations in other predisposing loci, i.e., disease markers, will constitute unambiguous diagnostic evidence and may immediately aid with patient management. Experimental assays developed in the course of the proposed study will contribute to diagnostic solutions that are available to schwannomatosis patients. Discovery of additional causal factors of schwannomatosis will increase the knowledge of the genetic basis of schwannomatosis and, along with funct
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610105
Entities
People
- Ludwine Messiaen
Organizations
- United States Army
- University of Alabama at Birmingham