Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

Chi Hong Wu, Claudia Fallini, Nicola Ticozzi, Pamela J. Keagle, Peter C. Sapp, Katarzyna Piotrowska, Patrick Lowe, Max Koppers, Diane McKenna-Yasek, Desiree M. Baron, Jason E. Kost, Paloma Gonzalez-Perez, Andrew D. Fox, Jenni Adams, Franco Taroni, Cinzia Tiloca, Ashley Lyn Leclerc, Shawn C. Chafe, Dev Mangroo, Melissa J. MooreJill A. Zitzewitz, Zuo Shang Xu, Leonard H. Van Den Berg, Jonathan D. Glass, Gabriele Siciliano, Elizabeth T. Cirulli, David B. Goldstein, Francois Salachas, Vincent Meininger, Wilfried Rossol, Antonia Ratti, Cinzia Gellera, Daryl A. Bosco, Gary J. Bassell, Vincenzo Silani, Vivian E. Drory, Robert H. Brown, John E. Landers

Research output: Contribution to journalArticle

321 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.

Original languageEnglish (US)
Pages (from-to)499-503
Number of pages5
JournalNature
Volume488
Issue number7412
DOIs
StatePublished - Aug 23 2012
Externally publishedYes

Fingerprint

Profilins
Amyotrophic Lateral Sclerosis
Mutation
Actins
Genes
Motor Neurons
Exome
Growth Cones
Neurodegenerative Diseases
Sequence Analysis
Amyotrophic lateral sclerosis 1

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Wu, C. H., Fallini, C., Ticozzi, N., Keagle, P. J., Sapp, P. C., Piotrowska, K., ... Landers, J. E. (2012). Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature, 488(7412), 499-503. https://doi.org/10.1038/nature11280

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. / Wu, Chi Hong; Fallini, Claudia; Ticozzi, Nicola; Keagle, Pamela J.; Sapp, Peter C.; Piotrowska, Katarzyna; Lowe, Patrick; Koppers, Max; McKenna-Yasek, Diane; Baron, Desiree M.; Kost, Jason E.; Gonzalez-Perez, Paloma; Fox, Andrew D.; Adams, Jenni; Taroni, Franco; Tiloca, Cinzia; Leclerc, Ashley Lyn; Chafe, Shawn C.; Mangroo, Dev; Moore, Melissa J.; Zitzewitz, Jill A.; Xu, Zuo Shang; Van Den Berg, Leonard H.; Glass, Jonathan D.; Siciliano, Gabriele; Cirulli, Elizabeth T.; Goldstein, David B.; Salachas, Francois; Meininger, Vincent; Rossol, Wilfried; Ratti, Antonia; Gellera, Cinzia; Bosco, Daryl A.; Bassell, Gary J.; Silani, Vincenzo; Drory, Vivian E.; Brown, Robert H.; Landers, John E.

In: Nature, Vol. 488, No. 7412, 23.08.2012, p. 499-503.

Research output: Contribution to journalArticle

Wu, CH, Fallini, C, Ticozzi, N, Keagle, PJ, Sapp, PC, Piotrowska, K, Lowe, P, Koppers, M, McKenna-Yasek, D, Baron, DM, Kost, JE, Gonzalez-Perez, P, Fox, AD, Adams, J, Taroni, F, Tiloca, C, Leclerc, AL, Chafe, SC, Mangroo, D, Moore, MJ, Zitzewitz, JA, Xu, ZS, Van Den Berg, LH, Glass, JD, Siciliano, G, Cirulli, ET, Goldstein, DB, Salachas, F, Meininger, V, Rossol, W, Ratti, A, Gellera, C, Bosco, DA, Bassell, GJ, Silani, V, Drory, VE, Brown, RH & Landers, JE 2012, 'Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis', Nature, vol. 488, no. 7412, pp. 499-503. https://doi.org/10.1038/nature11280
Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Aug 23;488(7412):499-503. https://doi.org/10.1038/nature11280
Wu, Chi Hong ; Fallini, Claudia ; Ticozzi, Nicola ; Keagle, Pamela J. ; Sapp, Peter C. ; Piotrowska, Katarzyna ; Lowe, Patrick ; Koppers, Max ; McKenna-Yasek, Diane ; Baron, Desiree M. ; Kost, Jason E. ; Gonzalez-Perez, Paloma ; Fox, Andrew D. ; Adams, Jenni ; Taroni, Franco ; Tiloca, Cinzia ; Leclerc, Ashley Lyn ; Chafe, Shawn C. ; Mangroo, Dev ; Moore, Melissa J. ; Zitzewitz, Jill A. ; Xu, Zuo Shang ; Van Den Berg, Leonard H. ; Glass, Jonathan D. ; Siciliano, Gabriele ; Cirulli, Elizabeth T. ; Goldstein, David B. ; Salachas, Francois ; Meininger, Vincent ; Rossol, Wilfried ; Ratti, Antonia ; Gellera, Cinzia ; Bosco, Daryl A. ; Bassell, Gary J. ; Silani, Vincenzo ; Drory, Vivian E. ; Brown, Robert H. ; Landers, John E. / Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. In: Nature. 2012 ; Vol. 488, No. 7412. pp. 499-503.
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abstract = "Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10{\%} of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50{\%} of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.",
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AU - Fallini, Claudia

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AU - Piotrowska, Katarzyna

AU - Lowe, Patrick

AU - Koppers, Max

AU - McKenna-Yasek, Diane

AU - Baron, Desiree M.

AU - Kost, Jason E.

AU - Gonzalez-Perez, Paloma

AU - Fox, Andrew D.

AU - Adams, Jenni

AU - Taroni, Franco

AU - Tiloca, Cinzia

AU - Leclerc, Ashley Lyn

AU - Chafe, Shawn C.

AU - Mangroo, Dev

AU - Moore, Melissa J.

AU - Zitzewitz, Jill A.

AU - Xu, Zuo Shang

AU - Van Den Berg, Leonard H.

AU - Glass, Jonathan D.

AU - Siciliano, Gabriele

AU - Cirulli, Elizabeth T.

AU - Goldstein, David B.

AU - Salachas, Francois

AU - Meininger, Vincent

AU - Rossol, Wilfried

AU - Ratti, Antonia

AU - Gellera, Cinzia

AU - Bosco, Daryl A.

AU - Bassell, Gary J.

AU - Silani, Vincenzo

AU - Drory, Vivian E.

AU - Brown, Robert H.

AU - Landers, John E.

PY - 2012/8/23

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N2 - Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.

AB - Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.

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