TY - JOUR
T1 - A dominant mutation in FBXO38 causes distal spinal muscular atrophy with calf predominance
AU - Sumner, Charlotte J.
AU - D'Ydewalle, Constantin
AU - Wooley, Joe
AU - Fawcett, Katherine A.
AU - Hernandez, Dena
AU - Gardiner, Alice R.
AU - Kalmar, Bernadett
AU - Baloh, Robert H.
AU - Gonzalez, Michael
AU - Züchner, Stephan
AU - Stanescu, Horia C.
AU - Kleta, Robert
AU - Mankodi, Ami
AU - Cornblath, David R.
AU - Boylan, Kevin B.
AU - Reilly, Mary M.
AU - Greensmith, Linda
AU - Singleton, Andrew B.
AU - Harms, Matthew B.
AU - Rossor, Alexander M.
AU - Houlden, Henry
N1 - Funding Information:
The authors would like to thank Kenneth Fischbeck for advice about genetics, Vinay Chaudhry and Zeng Wang for clinical care, Chris Dorsey and Jamal Garrison for muscle histology, and Peggy Allred for aid in DNA-sample collection. C.J.S. is supported by National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS062869. C.d.Y. is supported by the Research Council of KU Leuven (Special Research Fund). M.B.H. is funded by the NINDS (K08-NS-075094). A.M.R. is funded by the NINDS and Office of Rare Diseases (U54NS065712), as well as an Ipsen clinical research fellowship. H.H. is supported by The Wellcome Trust, the Muscular Dystrophy Campaign, the Medical Research Council, and The French Muscular Dystrophy Association. We would also like to thank the University College London Hospitals National Institute for Health Research Biomedical Research Centre funding scheme. This work was also supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (project ZO1 AG000958-10).
PY - 2013/11/7
Y1 - 2013/11/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2013.10.006
DO - 10.1016/j.ajhg.2013.10.006
M3 - Article
C2 - 24207122
AN - SCOPUS:84890167982
SN - 0002-9297
VL - 93
SP - 976
EP - 983
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -