Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype

Frances Theunissen; Ryan S. Anderton; Frank L. Mastaglia; Loren L. Flynn; Samantha J. Winter; Ian James; Richard Bedlack; Stuart Hodgetts; Sue Fletcher; Steve D. Wilton; Nigel G. Laing; Mandi MacShane; Merrilee Needham; Ann Saunders; Alan Mackay-Sim; Ze’ev Melamed; John Ravits; Don W. Cleveland; P. Anthony Akkari

doi:10.3389/fnagi.2021.658226

Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype

Frances Theunissen^*, Ryan S. Anderton, Frank L. Mastaglia, Loren L. Flynn, Samantha J. Winter, Ian James, Richard Bedlack, Stuart Hodgetts, Sue Fletcher, Steve D. Wilton, Nigel G. Laing, Mandi MacShane, Merrilee Needham, Ann Saunders, Alan Mackay-Sim, Ze’ev Melamed, John Ravits, Don W. Cleveland, P. Anthony Akkari^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Objective: There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration. Methods: The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons. Results: In a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons. Conclusions: We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

Original language	American English
Article number	658226
Journal	Frontiers in Aging Neuroscience
Volume	13
DOIs	https://doi.org/10.3389/fnagi.2021.658226
State	Published - 26 Mar 2021
Externally published	Yes

Bibliographical note

Funding Information:
We would like to acknowledge the patients that contribute to our ongoing work. We thank Ammar Al-Chalabi, Alfredo Iacoangeli, and Ahmad Al Khleifat for their thoughtful discussions, Julia Pytte and Leanne Jiang for their contribution toward the cohort allocations. Access to clinical data was facilitated by the SALSA-SGC project funded by the MNDRIA Ice Bucket Challenge Grant. Funding. This work was funded by the Perron Institute for Neurological and Translational Science, the Giumelli Foundation, Ian Potter Foundation, Racing for MNDi Foundation and the Pierce Armstrong Foundation. The olfactory neurosphere-derived cells were generated through funding to AM-S from the Australian Department of Health. NL is funded by Australian National Health and Medical Research (NHMRC) Fellowship (APP1117510). The funders had no role in the preparation of the manuscript and the decision to publish.

Funding Information:
This work was funded by the Perron Institute for Neurological and Translational Science, the Giumelli Foundation, Ian Potter

Funding Information:
We would like to acknowledge the patients that contribute to our ongoing work. We thank Ammar Al-Chalabi, Alfredo Iacoangeli, and Ahmad Al Khleifat for their thoughtful discussions, Julia Pytte and Leanne Jiang for their contribution toward the cohort allocations. Access to clinical data was facilitated by the SALSA-SGC project funded by the MNDRIA Ice Bucket Challenge Grant.

Publisher Copyright:
© Copyright © 2021 Theunissen, Anderton, Mastaglia, Flynn, Winter, James, Bedlack, Hodgetts, Fletcher, Wilton, Laing, MacShane, Needham, Saunders, Mackay-Sim, Melamed, Ravits, Cleveland and Akkari.

Keywords

amyotrophic lateral sclerosis
genetic association studies
genetic marker
genetic variant
motor neuron disease
stathmin-2
structural variation

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10.3389/fnagi.2021.658226

Cite this

Theunissen, F., Anderton, R. S., Mastaglia, F. L., Flynn, L. L., Winter, S. J., James, I., Bedlack, R., Hodgetts, S., Fletcher, S., Wilton, S. D., Laing, N. G., MacShane, M., Needham, M., Saunders, A., Mackay-Sim, A., Melamed, Z., Ravits, J., Cleveland, D. W., & Akkari, P. A. (2021). Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype. Frontiers in Aging Neuroscience, 13, Article 658226. https://doi.org/10.3389/fnagi.2021.658226

@article{94b033e3255344dbb950022d445602d7,

title = "Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype",

abstract = "Objective: There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration. Methods: The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons. Results: In a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons. Conclusions: We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.",

keywords = "amyotrophic lateral sclerosis, genetic association studies, genetic marker, genetic variant, motor neuron disease, stathmin-2, structural variation",

author = "Frances Theunissen and Anderton, {Ryan S.} and Mastaglia, {Frank L.} and Flynn, {Loren L.} and Winter, {Samantha J.} and Ian James and Richard Bedlack and Stuart Hodgetts and Sue Fletcher and Wilton, {Steve D.} and Laing, {Nigel G.} and Mandi MacShane and Merrilee Needham and Ann Saunders and Alan Mackay-Sim and Ze{\textquoteright}ev Melamed and John Ravits and Cleveland, {Don W.} and Akkari, {P. Anthony}",

note = "Funding Information: We would like to acknowledge the patients that contribute to our ongoing work. We thank Ammar Al-Chalabi, Alfredo Iacoangeli, and Ahmad Al Khleifat for their thoughtful discussions, Julia Pytte and Leanne Jiang for their contribution toward the cohort allocations. Access to clinical data was facilitated by the SALSA-SGC project funded by the MNDRIA Ice Bucket Challenge Grant. Funding. This work was funded by the Perron Institute for Neurological and Translational Science, the Giumelli Foundation, Ian Potter Foundation, Racing for MNDi Foundation and the Pierce Armstrong Foundation. The olfactory neurosphere-derived cells were generated through funding to AM-S from the Australian Department of Health. NL is funded by Australian National Health and Medical Research (NHMRC) Fellowship (APP1117510). The funders had no role in the preparation of the manuscript and the decision to publish. Funding Information: This work was funded by the Perron Institute for Neurological and Translational Science, the Giumelli Foundation, Ian Potter Funding Information: We would like to acknowledge the patients that contribute to our ongoing work. We thank Ammar Al-Chalabi, Alfredo Iacoangeli, and Ahmad Al Khleifat for their thoughtful discussions, Julia Pytte and Leanne Jiang for their contribution toward the cohort allocations. Access to clinical data was facilitated by the SALSA-SGC project funded by the MNDRIA Ice Bucket Challenge Grant. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Theunissen, Anderton, Mastaglia, Flynn, Winter, James, Bedlack, Hodgetts, Fletcher, Wilton, Laing, MacShane, Needham, Saunders, Mackay-Sim, Melamed, Ravits, Cleveland and Akkari.",

year = "2021",

month = mar,

day = "26",

doi = "10.3389/fnagi.2021.658226",

language = "American English",

volume = "13",

journal = "Frontiers in Aging Neuroscience",

issn = "1663-4365",

publisher = "Frontiers Media S.A.",

}

Theunissen, F, Anderton, RS, Mastaglia, FL, Flynn, LL, Winter, SJ, James, I, Bedlack, R, Hodgetts, S, Fletcher, S, Wilton, SD, Laing, NG, MacShane, M, Needham, M, Saunders, A, Mackay-Sim, A, Melamed, Z, Ravits, J, Cleveland, DW & Akkari, PA 2021, 'Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype', Frontiers in Aging Neuroscience, vol. 13, 658226. https://doi.org/10.3389/fnagi.2021.658226

TY - JOUR

T1 - Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype

AU - Theunissen, Frances

AU - Anderton, Ryan S.

AU - Mastaglia, Frank L.

AU - Flynn, Loren L.

AU - Winter, Samantha J.

AU - James, Ian

AU - Bedlack, Richard

AU - Hodgetts, Stuart

AU - Fletcher, Sue

AU - Wilton, Steve D.

AU - Laing, Nigel G.

AU - MacShane, Mandi

AU - Needham, Merrilee

AU - Saunders, Ann

AU - Mackay-Sim, Alan

AU - Melamed, Ze’ev

AU - Ravits, John

AU - Cleveland, Don W.

AU - Akkari, P. Anthony

N1 - Funding Information: We would like to acknowledge the patients that contribute to our ongoing work. We thank Ammar Al-Chalabi, Alfredo Iacoangeli, and Ahmad Al Khleifat for their thoughtful discussions, Julia Pytte and Leanne Jiang for their contribution toward the cohort allocations. Access to clinical data was facilitated by the SALSA-SGC project funded by the MNDRIA Ice Bucket Challenge Grant. Funding. This work was funded by the Perron Institute for Neurological and Translational Science, the Giumelli Foundation, Ian Potter Foundation, Racing for MNDi Foundation and the Pierce Armstrong Foundation. The olfactory neurosphere-derived cells were generated through funding to AM-S from the Australian Department of Health. NL is funded by Australian National Health and Medical Research (NHMRC) Fellowship (APP1117510). The funders had no role in the preparation of the manuscript and the decision to publish. Funding Information: This work was funded by the Perron Institute for Neurological and Translational Science, the Giumelli Foundation, Ian Potter Funding Information: We would like to acknowledge the patients that contribute to our ongoing work. We thank Ammar Al-Chalabi, Alfredo Iacoangeli, and Ahmad Al Khleifat for their thoughtful discussions, Julia Pytte and Leanne Jiang for their contribution toward the cohort allocations. Access to clinical data was facilitated by the SALSA-SGC project funded by the MNDRIA Ice Bucket Challenge Grant. Publisher Copyright: © Copyright © 2021 Theunissen, Anderton, Mastaglia, Flynn, Winter, James, Bedlack, Hodgetts, Fletcher, Wilton, Laing, MacShane, Needham, Saunders, Mackay-Sim, Melamed, Ravits, Cleveland and Akkari.

PY - 2021/3/26

Y1 - 2021/3/26

N2 - Objective: There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration. Methods: The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons. Results: In a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons. Conclusions: We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

AB - Objective: There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration. Methods: The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons. Results: In a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons. Conclusions: We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

KW - amyotrophic lateral sclerosis

KW - genetic association studies

KW - genetic marker

KW - genetic variant

KW - motor neuron disease

KW - stathmin-2

KW - structural variation

UR - http://www.scopus.com/inward/record.url?scp=85103915439&partnerID=8YFLogxK

U2 - 10.3389/fnagi.2021.658226

DO - 10.3389/fnagi.2021.658226

M3 - Article

C2 - 33841129

AN - SCOPUS:85103915439

SN - 1663-4365

VL - 13

JO - Frontiers in Aging Neuroscience

JF - Frontiers in Aging Neuroscience

M1 - 658226

ER -

Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype

Abstract

Bibliographical note

Keywords

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