A dominant mutation in FBXO38 causes distal spinal muscular atrophy with calf predominance

Charlotte J. Sumner, Constantin D'Ydewalle, Joe Wooley, Katherine A. Fawcett, Dena Hernandez, Alice R. Gardiner, Bernadett Kalmar, Robert H. Baloh, Michael Gonzalez, Stephan Züchner, Horia C. Stanescu, Robert Kleta, Ami Mankodi, David R. Cornblath, Kevin B. Boylan, Mary M. Reilly, Linda Greensmith, Andrew B. Singleton, Matthew B. Harms, Alexander M. RossorHenry Houlden

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Spinal muscular atrophies (SMAs) are a heterogeneous group of inherited disorders characterized by degeneration of anterior horn cells and progressive muscle weakness. In two unrelated families affected by a distinct form of autosomal-dominant distal SMA initially manifesting with calf weakness, we identified by genetic linkage analysis and exome sequencing a heterozygous missense mutation, c.616T>C (p.Cys206Arg), in F-box protein 38 (FBXO38). FBXO38 is a known coactivator of the transcription factor Krüppel-like factor 7 (KLF7), which regulates genes required for neuronal axon outgrowth and repair. The p.Cys206Arg substitution did not alter the subcellular localization of FBXO38 but did impair KLF7-mediated transactivation of a KLF7-responsive promoter construct and endogenous KLF7 target genes in both heterologously expressing human embryonic kidney 293T cells and fibroblasts derived from individuals with the FBXO38 missense mutation. This transcriptional dysregulation was associated with an impairment of neurite outgrowth in primary motor neurons. Together, these results suggest that a transcriptional regulatory pathway that has a well-established role in axonal development could also be critical for neuronal maintenance and highlight the importance of FBXO38 and KLF7 activity in motor neurons.

Original languageEnglish (US)
Pages (from-to)976-983
Number of pages8
JournalAmerican journal of human genetics
Volume93
Issue number5
DOIs
StatePublished - Nov 7 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Sumner, C. J., D'Ydewalle, C., Wooley, J., Fawcett, K. A., Hernandez, D., Gardiner, A. R., Kalmar, B., Baloh, R. H., Gonzalez, M., Züchner, S., Stanescu, H. C., Kleta, R., Mankodi, A., Cornblath, D. R., Boylan, K. B., Reilly, M. M., Greensmith, L., Singleton, A. B., Harms, M. B., ... Houlden, H. (2013). A dominant mutation in FBXO38 causes distal spinal muscular atrophy with calf predominance. American journal of human genetics, 93(5), 976-983. https://doi.org/10.1016/j.ajhg.2013.10.006