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

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

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. 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.

Original languageEnglish (US)
Pages (from-to)182-187
Number of pages6
JournalNature Genetics
Volume46
Issue number2
DOIs
StatePublished - Jan 1 2014

Fingerprint

Neurilemmoma
Mutation
Germ-Line Mutation
Alleles
Loss of Heterozygosity
Genes
Schwannomatosis
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., ... Messiaen, L. M. (2014). Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nature Genetics, 46(2), 182-187. https://doi.org/10.1038/ng.2855

Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. / Piotrowski, Arkadiusz; Xie, Jing; Liu, Ying F.; Poplawski, Andrzej B.; Gomes, Alicia R.; Madanecki, Piotr; Fu, Chuanhua; Crowley, Michael R.; Crossman, David K.; Armstrong, Linlea; Babovic-Vuksanovic, Dusica; Bergner, Amanda; Blakeley, Jaishri O.; Blumenthal, Andrea L.; Daniels, Molly S.; Feit, Howard; Gardner, Kathy; Hurst, Stephanie; Kobelka, Christine; Lee, Chung; Nagy, Rebecca; Rauen, Katherine A.; Slopis, John M.; Suwannarat, Pim; Westman, Judith A.; Zanko, Andrea; Korf, Bruce R.; Messiaen, Ludwine M.

In: Nature Genetics, Vol. 46, No. 2, 01.01.2014, p. 182-187.

Research output: Contribution to journalArticle

Piotrowski, A, Xie, J, Liu, YF, Poplawski, AB, Gomes, AR, Madanecki, P, Fu, C, Crowley, MR, Crossman, DK, Armstrong, L, Babovic-Vuksanovic, D, Bergner, A, Blakeley, JO, Blumenthal, AL, Daniels, MS, Feit, H, Gardner, K, Hurst, S, Kobelka, C, Lee, C, Nagy, R, Rauen, KA, Slopis, JM, Suwannarat, P, Westman, JA, Zanko, A, Korf, BR & Messiaen, LM 2014, 'Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas', Nature Genetics, vol. 46, no. 2, pp. 182-187. https://doi.org/10.1038/ng.2855
Piotrowski A, Xie J, Liu YF, Poplawski AB, Gomes AR, Madanecki P et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nature Genetics. 2014 Jan 1;46(2):182-187. https://doi.org/10.1038/ng.2855
Piotrowski, Arkadiusz ; Xie, Jing ; Liu, Ying F. ; Poplawski, Andrzej B. ; Gomes, Alicia R. ; Madanecki, Piotr ; Fu, Chuanhua ; Crowley, Michael R. ; Crossman, David K. ; Armstrong, Linlea ; Babovic-Vuksanovic, Dusica ; Bergner, Amanda ; Blakeley, Jaishri O. ; Blumenthal, Andrea L. ; Daniels, Molly S. ; Feit, Howard ; Gardner, Kathy ; Hurst, Stephanie ; Kobelka, Christine ; Lee, Chung ; Nagy, Rebecca ; Rauen, Katherine A. ; Slopis, John M. ; Suwannarat, Pim ; Westman, Judith A. ; Zanko, Andrea ; Korf, Bruce R. ; Messiaen, Ludwine M. / Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. In: Nature Genetics. 2014 ; Vol. 46, No. 2. pp. 182-187.
@article{6ee33d2611de4ae883b6686d3301f908,
title = "Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas",
abstract = "Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50{\%} of familial and <10{\%} of sporadic schwannomatosis cases. 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.",
author = "Arkadiusz Piotrowski and Jing Xie and Liu, {Ying F.} and Poplawski, {Andrzej B.} and Gomes, {Alicia R.} and Piotr Madanecki and Chuanhua Fu and Crowley, {Michael R.} and Crossman, {David K.} and Linlea Armstrong and Dusica Babovic-Vuksanovic and Amanda Bergner and Blakeley, {Jaishri O.} and Blumenthal, {Andrea L.} and Daniels, {Molly S.} and Howard Feit and Kathy Gardner and Stephanie Hurst and Christine Kobelka and Chung Lee and Rebecca Nagy and Rauen, {Katherine A.} and Slopis, {John M.} and Pim Suwannarat and Westman, {Judith A.} and Andrea Zanko and Korf, {Bruce R.} and Messiaen, {Ludwine M.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1038/ng.2855",
language = "English (US)",
volume = "46",
pages = "182--187",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas

AU - Piotrowski, Arkadiusz

AU - Xie, Jing

AU - Liu, Ying F.

AU - Poplawski, Andrzej B.

AU - Gomes, Alicia R.

AU - Madanecki, Piotr

AU - Fu, Chuanhua

AU - Crowley, Michael R.

AU - Crossman, David K.

AU - Armstrong, Linlea

AU - Babovic-Vuksanovic, Dusica

AU - Bergner, Amanda

AU - Blakeley, Jaishri O.

AU - Blumenthal, Andrea L.

AU - Daniels, Molly S.

AU - Feit, Howard

AU - Gardner, Kathy

AU - Hurst, Stephanie

AU - Kobelka, Christine

AU - Lee, Chung

AU - Nagy, Rebecca

AU - Rauen, Katherine A.

AU - Slopis, John M.

AU - Suwannarat, Pim

AU - Westman, Judith A.

AU - Zanko, Andrea

AU - Korf, Bruce R.

AU - Messiaen, Ludwine M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. 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.

AB - Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. 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.

UR - http://www.scopus.com/inward/record.url?scp=84895825681&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895825681&partnerID=8YFLogxK

U2 - 10.1038/ng.2855

DO - 10.1038/ng.2855

M3 - Article

C2 - 24362817

AN - SCOPUS:84895825681

VL - 46

SP - 182

EP - 187

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 2

ER -