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. 2015 Jul;23(7):963-8.
doi: 10.1038/ejhg.2014.220. Epub 2014 Oct 22.

Expanding the mutational spectrum of LZTR1 in schwannomatosis

Irene Paganini  1 , Vivian Y Chang  2 , Gabriele L Capone  3 , Jeremie Vitte  4 , Matteo Benelli  5 , Lorenzo Barbetti  1 , Roberta Sestini  1 , Eva Trevisson  6 , Theo Jm Hulsebos  7 , Marco Giovannini  4 , Stanley F Nelson  8 , Laura Papi  1
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Expanding the mutational spectrum of LZTR1 in schwannomatosis

Irene Paganini et al. Eur J Hum Genet. 2015 Jul.

Abstract

Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.

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Figures

Figure 1
Figure 1
Sequence analysis of LZTR1 in blood and tumors of mutated patients. Asterisks indicate subjects in the family who carry the variant. (a) The frameshift variant in exon 13 of LZTR1 was detected in the genomic DNA from the proband (arrow) and his affected father. The variant was present in the proband's schwannoma T714, which retained both alleles. (b) The frameshift variant in exon 16 of LZTR1 is present in the proband and her unaffected father and is retained in two schwannomas. (c) A frameshift variant in exon 14, c.1602delA (p.Lys534Asnfs*22), was identified in the proband from family 307 and his unaffected father, but not in the affected brother. The altered LZTR1 allele was retained in two tumors of the brother. Haplotype analysis for chromosome 22 markers in the family clearly indicated that the affected siblings inherited the two different chromosomes 22 from their father.
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