Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany

S Waibel; M Neumann; A Rosenbohm; A Birve; A E Volk; J H Weishaupt; T Meyer; U Müller; P M Andersen; A C Ludolph

doi:10.1111/ene.12031

Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations

Standard

Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations : a clinico-genetic study in Germany. / Waibel, S; Neumann, M; Rosenbohm, A; Birve, A; Volk, A E; Weishaupt, J H; Meyer, T; Müller, U; Andersen, P M; Ludolph, A C.

In: EUR J NEUROL, Vol. 20, No. 3, 03.2013, p. 540-6.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Waibel, S, Neumann, M, Rosenbohm, A, Birve, A, Volk, AE, Weishaupt, JH, Meyer, T, Müller, U, Andersen, PM & Ludolph, AC 2013, 'Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany', EUR J NEUROL, vol. 20, no. 3, pp. 540-6. https://doi.org/10.1111/ene.12031

APA

Waibel, S., Neumann, M., Rosenbohm, A., Birve, A., Volk, A. E., Weishaupt, J. H., Meyer, T., Müller, U., Andersen, P. M., & Ludolph, A. C. (2013). Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany. EUR J NEUROL, 20(3), 540-6. https://doi.org/10.1111/ene.12031

Vancouver

Waibel S, Neumann M, Rosenbohm A, Birve A, Volk AE, Weishaupt JH et al. Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany. EUR J NEUROL. 2013 Mar;20(3):540-6. https://doi.org/10.1111/ene.12031

Bibtex

@article{3609d1ddf8424543a3a7078e36ab1eb1,

title = "Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany",

abstract = "BACKGROUND AND PURPOSE: Mutations in the FUS/TLS have been associated with amyotrophic lateral sclerosis (ALS) in a few percent of patients.METHODS: We screened 184 familial (FALS) and 200 sporadic German patients with ALS for FUS/TLS mutations by sequence analysis of exons 5, 6 and 13-15. We compared the phenotypes of patients with different FUS/TLS mutations.RESULTS: We identified three missense mutations p.K510R, p.R514G, p.R521H, and the two truncating mutations p.R495X and p.G478LfsX23 in samples from eight pedigrees. Both truncating mutations were associated with young onset and very aggressive disease courses, whereas the p.R521H, p.R514G and in particular the p.K510R mutation showed a milder phenotype with disease durations ranging from 3 years to more than 26 years, the longest reported for a patient with a FUS/TLS mutation. Also, in a pair of monozygous twins with the p.K510R mutation, a remarkable similar disease course was observed.CONCLUSIONS: Mutations in FUS/TLS account for 8.7% (16 of 184) of FALS in Germany. This is a higher prevalence than reported from other countries. Truncating FUS/TLS mutations result in a more severe phenotype than most missense mutations. The wide phenotypic differences have implications for genetic counselling.",

keywords = "Adult, Amyotrophic Lateral Sclerosis, Disease Progression, Female, Genotype, Germany, Humans, Male, Middle Aged, Mutation, Pedigree, Phenotype, RNA-Binding Protein FUS, Reverse Transcriptase Polymerase Chain Reaction",

author = "S Waibel and M Neumann and A Rosenbohm and A Birve and Volk, {A E} and Weishaupt, {J H} and T Meyer and U M{\"u}ller and Andersen, {P M} and Ludolph, {A C}",

note = "{\textcopyright} 2012 The Author(s) European Journal of Neurology {\textcopyright} 2012 EFNS.",

year = "2013",

month = mar,

doi = "10.1111/ene.12031",

language = "English",

volume = "20",

pages = "540--6",

journal = "EUR J NEUROL",

issn = "1351-5101",

publisher = "Wiley-Blackwell",

number = "3",

}

RIS

TY - JOUR

T1 - Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations

T2 - a clinico-genetic study in Germany

AU - Waibel, S

AU - Neumann, M

AU - Rosenbohm, A

AU - Birve, A

AU - Volk, A E

AU - Weishaupt, J H

AU - Meyer, T

AU - Müller, U

AU - Andersen, P M

AU - Ludolph, A C

PY - 2013/3

Y1 - 2013/3

N2 - BACKGROUND AND PURPOSE: Mutations in the FUS/TLS have been associated with amyotrophic lateral sclerosis (ALS) in a few percent of patients.METHODS: We screened 184 familial (FALS) and 200 sporadic German patients with ALS for FUS/TLS mutations by sequence analysis of exons 5, 6 and 13-15. We compared the phenotypes of patients with different FUS/TLS mutations.RESULTS: We identified three missense mutations p.K510R, p.R514G, p.R521H, and the two truncating mutations p.R495X and p.G478LfsX23 in samples from eight pedigrees. Both truncating mutations were associated with young onset and very aggressive disease courses, whereas the p.R521H, p.R514G and in particular the p.K510R mutation showed a milder phenotype with disease durations ranging from 3 years to more than 26 years, the longest reported for a patient with a FUS/TLS mutation. Also, in a pair of monozygous twins with the p.K510R mutation, a remarkable similar disease course was observed.CONCLUSIONS: Mutations in FUS/TLS account for 8.7% (16 of 184) of FALS in Germany. This is a higher prevalence than reported from other countries. Truncating FUS/TLS mutations result in a more severe phenotype than most missense mutations. The wide phenotypic differences have implications for genetic counselling.

AB - BACKGROUND AND PURPOSE: Mutations in the FUS/TLS have been associated with amyotrophic lateral sclerosis (ALS) in a few percent of patients.METHODS: We screened 184 familial (FALS) and 200 sporadic German patients with ALS for FUS/TLS mutations by sequence analysis of exons 5, 6 and 13-15. We compared the phenotypes of patients with different FUS/TLS mutations.RESULTS: We identified three missense mutations p.K510R, p.R514G, p.R521H, and the two truncating mutations p.R495X and p.G478LfsX23 in samples from eight pedigrees. Both truncating mutations were associated with young onset and very aggressive disease courses, whereas the p.R521H, p.R514G and in particular the p.K510R mutation showed a milder phenotype with disease durations ranging from 3 years to more than 26 years, the longest reported for a patient with a FUS/TLS mutation. Also, in a pair of monozygous twins with the p.K510R mutation, a remarkable similar disease course was observed.CONCLUSIONS: Mutations in FUS/TLS account for 8.7% (16 of 184) of FALS in Germany. This is a higher prevalence than reported from other countries. Truncating FUS/TLS mutations result in a more severe phenotype than most missense mutations. The wide phenotypic differences have implications for genetic counselling.

KW - Adult

KW - Amyotrophic Lateral Sclerosis

KW - Disease Progression

KW - Female

KW - Genotype

KW - Germany

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Pedigree

KW - Phenotype

KW - RNA-Binding Protein FUS

KW - Reverse Transcriptase Polymerase Chain Reaction

U2 - 10.1111/ene.12031

DO - 10.1111/ene.12031

M3 - SCORING: Journal article

C2 - 23217123

VL - 20

SP - 540

EP - 546

JO - EUR J NEUROL

JF - EUR J NEUROL

SN - 1351-5101

IS - 3

ER -