title: Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2.
abstract: Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders.
authors.affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Buckley
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Mantripragada
authors.forename: Teresita
authors.initials: T
authors.lastname: Díaz de Ståhl
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Piotrowski
authors.forename: Caisa M
authors.initials: CM
authors.lastname: Hansson
authors.forename: Hajnalka
authors.initials: H
authors.lastname: Kiss
authors.forename: David
authors.initials: D
authors.lastname: Vetrie
authors.forename: Ingemar T
authors.initials: IT
authors.lastname: Ernberg
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: Lars
authors.initials: L
authors.lastname: Bolund
authors.forename: Markku
authors.initials: M
authors.lastname: Sainio
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Michihito
authors.initials: M
authors.lastname: Niimura
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wallace
authors.forename: D Gareth R
authors.initials: DG
authors.lastname: Evans
authors.forename: Gintautas
authors.initials: G
authors.lastname: Grigelionis
authors.forename: Uwe
authors.initials: U
authors.lastname: Menzel
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019703:Calcineurin / Q000235:genetics; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D019295:Computational Biology; D003937:Diagnosis, Differential; D018628:Gene Dosage; D015321:Gene Rearrangement; D016515:Genes, Neurofibromatosis 2; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D046228:Microarray Analysis; D009154:Mutation; D009442:Neurilemmoma / Q000175:diagnosis / Q000235:genetics*; D016518:Neurofibromatosis 2 / Q000175:diagnosis / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D011110:Polymorphism, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D007146:Immunoglobulin lambda-Chains; D010750:Phosphoproteins; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D019703:Calcineurin