Journal Article

Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas

Poplawski, Andrzej B, Korf, Bruce R, Piotrowski, Arkadiusz, Rauen, Katherine A, Messiaen, Ludwine M, Daniels, Molly S, Fu, Chuanhua, Babovic-Vuksanovic, Dusica, Nagy, Rebecca, Liu, Ying F, Gomes, Alicia R, Lee, Chung, Bergner, Amanda, Slopis, John M, Crowley, Michael R, Blakeley, Jaishri O, Gardner, Kathy, Zanko, Andrea, Westman, Judith A, Xie, Jing, Blumenthal, Andrea L, Hurst, Stephanie, Armstrong, Linlea, Madanecki, Piotr, Feit, Howard, Suwannarat, Pim, Crossman, David K, Kobelka, Christine

2014

Overview

Ludwine Messiaen and colleagues report the identification of constitutional LZTR1 mutations in individuals with schwannomatosis, an autosomal dominant inherited disorder of multiple schwannomas. Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases 1 . We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2 , with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ∼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1 .

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/23 / 38/77 / 38/88 / 38/91 / 631/1647/514/1948 / 631/208 / 692/699/67 / Agriculture / Animal Genetics and Genomics / Base Sequence / Biomedicine / Cancer Research / Chromosomal Proteins, Non-Histone - genetics / Chromosomes, Human, Pair 22 - genetics / DNA, Complementary - genetics / DNA-Binding Proteins - genetics / Gene Components / Gene Function / Gene mutations / Genes / Genes, Dominant - genetics / Genetic aspects / Genetic Predisposition to Disease - genetics / Germ-Line Mutation - genetics / Health aspects / Human Genetics / Humans / letter / Loss of Heterozygosity / Microsatellite Repeats - genetics / Models, Molecular / Molecular Sequence Data / Mutation / Neurilemmoma - genetics / Neurofibromatosis / Neurofibromatosis 2 - genetics / NMR / Nuclear magnetic resonance / Pedigree / Protein Conformation / Proteins / Retention / Risk factors / Sequence Analysis, DNA / SMARCB1 Protein / Studies / Transcription Factors - chemistry / Transcription Factors - genetics / Tumors