Neurobiology of Aging 36 (2015) 546.e15e546.e16
Contents lists available at ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Negative results
A UBQLN2 variant of unknown significance in frontotemporal lobar degeneration Francis Ugwu a, Sara Rollinson a, Jenny Harris a, b, Alex Gerhard a, b, Anna Richardson a, b, Matt Jones a, b, David Mann a, b, Julie Snowden a, b, Stuart Pickering-Brown a, * a b
Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK Institute of Brain, Behaviour and Mental Health, Salford Royal Hospital, Salford, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 July 2014 Received in revised form 28 July 2014 Accepted 1 August 2014 Available online 6 August 2014
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered to be part of a disease spectrum. However, with the exception of C9orf72, genes that cause ALS are rarely found to cause FTD and vice versa. To investigate this further, we have sequenced the ALS gene UBQLN2 in our FTD cohort and have found a single putative mutation. This further supports the concept that ALS genes are a rare cause of FTD. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: UBQLN2 Frontotemporal dementia Amyotrophic lateral sclerosis FTD ALS
1. Introduction Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have, for many years, been considered to form part of a spectrum (Talbot et al., 1995). However, genes causing one end of the spectrum are seldom found causing disease at the other end; however, in rare cases p62 and VCP can be found in both (Bennion Callister and Pickering-Brown, 2014). Recently, Deng et al. (2011) reported mutations in the UBQLN2 gene on the X chromosome, in some familial cases of ALS and ALS and/or dementia. UBQLN2 is a component of the protein inclusions present in the spinal cord and brain of patients with ALS and/or dementia. In this study, we have assessed whether UBQLN2 mutations are also present in a cohort of patients with FTD to further establish shared genetic etiology. 2. Methods The study involved 361 patients with clinically diagnosed FTD who had been investigated at the Cerebral Function Unit, Salford * Corresponding author at: Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester M139PT, UK. Tel.: þ44 (0) 161 275 1341; fax: þ44 (0) 161 275 3938. E-mail address: [email protected] (S. Pickering-Brown). 0197-4580/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.08.002
Royal Foundation Trust in accordance with Lund-Manchester criteria, and the presence of coexisting ALS was noted. Ethics approval was obtained from the Greater Manchester North research ethics committee. Clinical diagnosis was confirmed pathologically in 73 cases. The open reading frame of UBQLN2 was sequenced in all patients as previously described by Deng et al. (2011), with a small modification of the addition of these 2 extra amplicons. Ubqln2-3F: 50 -gacctggctcttagcaatctag-30 ; Ubqln2-3R: 50 -gtgtct ggattctgcatctgc-30 . Ubqln2-4F: 50 -cacagatgatgctgaatagcc-30 ; Ubqln2-4R: 50 -gctgaat gaactgctggttgg-30 . 3. Results and discussion After excluding 45 patients which had known mutations in MAPT, GRN, or C9ORF72 from further analysis 316 patients remained. One hundred seventy-seven of the patients were male (age range of 35e80 years, mean of 60.1 years), 138 were female (age range of 24e83 years, mean of 61.1 years). Forty-one had coexisting ALS. Three different UBQLN2 variations were observed in 5 unrelated patients (Table 1). We detected 2 different silent changes, and because they were not close to splice sites we consider these not to be pathogenic. The only coding variant
546.e16
F. Ugwu et al. / Neurobiology of Aging 36 (2015) 546.e15e546.e16
Table 1 Nucleotide variants found in the Manchester cohort of FTD patients Nucleotide variants
Protein variants
Heterozygous/homozygous (sex)
Frequency in cases (n ¼ 316)
Present in controls (n z 7000)
Conserved
SIFT analysis
c.1681C>T c.1736G>A c.1742C>A
p.T467I p.L485L p.T487T
Homo. (F) Homo. (M) Het. (F)
1 1 3
No No Yes
Yes N/A N/A
Tolerated N/A N/A
Key: F, female; FTD, frontotemporal dementia; M, male; N/A, not applicable.
present is a potential novel pathogenic mutation (c.1681C>T), causing a threonine 467 to isoleucine change (T467I) in the protein. This was present in a 70-year-old woman with FTD with known family history of dementia but none of ALS. The mutation was absent in dbSNP, the 1000 genomes project and the ESP database (n z 5500). The T467I mutation, upstream from the PXX repeat region of the protein, affects a highly conserved residue and is highly conserved in all 8 species examined: human, chimp, gibbon, rabbit, gorilla, bushbaby, dog, mouse, and rat. However, this change was predicted to be tolerated by SIFT bioinformatics analysis. In the absence of pathologic confirmation of disease, and segregation with other family members, the pathogenicity of this novel mutation cannot be confirmed until the effect of the mutation on protein function has been investigated. It is important to establish whether UBQLN2 is one component involved in a common disease-causing pathway shared between FTD and ALS. However, this finding supports the concept that genes causing ALS are rarely found to cause FTD.
Disclosure statement The authors have no conflicts of interest to disclose. Acknowledgements This work was funded by the Medical Research Council (G0701441), UK. References Bennion Callister, J., Pickering-Brown, S.M., 2014. Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. Exp. Neurol. [June 8th Epub ahead of print]. Deng, H.X., Chen, W., Hong, S.T., Boycott, K.M., Gorrie, G.H., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G.H., Donkervoort, S., Bigio, E.H., Brooks, B.R., Ajroud, K., Sufit, R.L., Haines, J.L., Mugnaini, E., PericakVance, M.A., Siddique, T., 2011. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211e215. Talbot, P.R., Goulding, P.J., Lloyd, J.J., Snowden, J.S., Neary, D., Testa, H.J., 1995. Interrelation between “classic” motor neuron disease and frontotemporal dementia: neuropsychological and single photon emission computed tomography study. J. Neurol. Neurosurg. Psychiatry 58, 541e547.
Contents lists available at ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Negative results
A UBQLN2 variant of unknown significance in frontotemporal lobar degeneration Francis Ugwu a, Sara Rollinson a, Jenny Harris a, b, Alex Gerhard a, b, Anna Richardson a, b, Matt Jones a, b, David Mann a, b, Julie Snowden a, b, Stuart Pickering-Brown a, * a b
Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK Institute of Brain, Behaviour and Mental Health, Salford Royal Hospital, Salford, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 July 2014 Received in revised form 28 July 2014 Accepted 1 August 2014 Available online 6 August 2014
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered to be part of a disease spectrum. However, with the exception of C9orf72, genes that cause ALS are rarely found to cause FTD and vice versa. To investigate this further, we have sequenced the ALS gene UBQLN2 in our FTD cohort and have found a single putative mutation. This further supports the concept that ALS genes are a rare cause of FTD. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: UBQLN2 Frontotemporal dementia Amyotrophic lateral sclerosis FTD ALS
1. Introduction Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have, for many years, been considered to form part of a spectrum (Talbot et al., 1995). However, genes causing one end of the spectrum are seldom found causing disease at the other end; however, in rare cases p62 and VCP can be found in both (Bennion Callister and Pickering-Brown, 2014). Recently, Deng et al. (2011) reported mutations in the UBQLN2 gene on the X chromosome, in some familial cases of ALS and ALS and/or dementia. UBQLN2 is a component of the protein inclusions present in the spinal cord and brain of patients with ALS and/or dementia. In this study, we have assessed whether UBQLN2 mutations are also present in a cohort of patients with FTD to further establish shared genetic etiology. 2. Methods The study involved 361 patients with clinically diagnosed FTD who had been investigated at the Cerebral Function Unit, Salford * Corresponding author at: Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester M139PT, UK. Tel.: þ44 (0) 161 275 1341; fax: þ44 (0) 161 275 3938. E-mail address: [email protected] (S. Pickering-Brown). 0197-4580/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.08.002
Royal Foundation Trust in accordance with Lund-Manchester criteria, and the presence of coexisting ALS was noted. Ethics approval was obtained from the Greater Manchester North research ethics committee. Clinical diagnosis was confirmed pathologically in 73 cases. The open reading frame of UBQLN2 was sequenced in all patients as previously described by Deng et al. (2011), with a small modification of the addition of these 2 extra amplicons. Ubqln2-3F: 50 -gacctggctcttagcaatctag-30 ; Ubqln2-3R: 50 -gtgtct ggattctgcatctgc-30 . Ubqln2-4F: 50 -cacagatgatgctgaatagcc-30 ; Ubqln2-4R: 50 -gctgaat gaactgctggttgg-30 . 3. Results and discussion After excluding 45 patients which had known mutations in MAPT, GRN, or C9ORF72 from further analysis 316 patients remained. One hundred seventy-seven of the patients were male (age range of 35e80 years, mean of 60.1 years), 138 were female (age range of 24e83 years, mean of 61.1 years). Forty-one had coexisting ALS. Three different UBQLN2 variations were observed in 5 unrelated patients (Table 1). We detected 2 different silent changes, and because they were not close to splice sites we consider these not to be pathogenic. The only coding variant
546.e16
F. Ugwu et al. / Neurobiology of Aging 36 (2015) 546.e15e546.e16
Table 1 Nucleotide variants found in the Manchester cohort of FTD patients Nucleotide variants
Protein variants
Heterozygous/homozygous (sex)
Frequency in cases (n ¼ 316)
Present in controls (n z 7000)
Conserved
SIFT analysis
c.1681C>T c.1736G>A c.1742C>A
p.T467I p.L485L p.T487T
Homo. (F) Homo. (M) Het. (F)
1 1 3
No No Yes
Yes N/A N/A
Tolerated N/A N/A
Key: F, female; FTD, frontotemporal dementia; M, male; N/A, not applicable.
present is a potential novel pathogenic mutation (c.1681C>T), causing a threonine 467 to isoleucine change (T467I) in the protein. This was present in a 70-year-old woman with FTD with known family history of dementia but none of ALS. The mutation was absent in dbSNP, the 1000 genomes project and the ESP database (n z 5500). The T467I mutation, upstream from the PXX repeat region of the protein, affects a highly conserved residue and is highly conserved in all 8 species examined: human, chimp, gibbon, rabbit, gorilla, bushbaby, dog, mouse, and rat. However, this change was predicted to be tolerated by SIFT bioinformatics analysis. In the absence of pathologic confirmation of disease, and segregation with other family members, the pathogenicity of this novel mutation cannot be confirmed until the effect of the mutation on protein function has been investigated. It is important to establish whether UBQLN2 is one component involved in a common disease-causing pathway shared between FTD and ALS. However, this finding supports the concept that genes causing ALS are rarely found to cause FTD.
Disclosure statement The authors have no conflicts of interest to disclose. Acknowledgements This work was funded by the Medical Research Council (G0701441), UK. References Bennion Callister, J., Pickering-Brown, S.M., 2014. Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. Exp. Neurol. [June 8th Epub ahead of print]. Deng, H.X., Chen, W., Hong, S.T., Boycott, K.M., Gorrie, G.H., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G.H., Donkervoort, S., Bigio, E.H., Brooks, B.R., Ajroud, K., Sufit, R.L., Haines, J.L., Mugnaini, E., PericakVance, M.A., Siddique, T., 2011. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211e215. Talbot, P.R., Goulding, P.J., Lloyd, J.J., Snowden, J.S., Neary, D., Testa, H.J., 1995. Interrelation between “classic” motor neuron disease and frontotemporal dementia: neuropsychological and single photon emission computed tomography study. J. Neurol. Neurosurg. Psychiatry 58, 541e547.
