Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 5, Pages 976-983Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.10.006
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Funding
- National Institute of Neurological Disorders and Stroke (NINDS) [R01NS062869]
- Research Council of KU Leuven
- NINDS [K08-NS-075094]
- Office of Rare Diseases [U54NS065712]
- Ipsen clinical research fellowship
- Wellcome Trust
- Muscular Dystrophy Campaign
- Medical Research Council
- French Muscular Dystrophy Association
- National Institute on Aging, National Institutes of Health, Department of Health and Human Services [ZO1 AG000958-10]
- MRC [G108/638, G1001253, MR/J004758/1, G0802760, MR/K000608/1] Funding Source: UKRI
- Medical Research Council [MR/J004758/1, G108/638, MR/K000608/1, G0802760, G1001253] Funding Source: researchfish
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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 Kruppel-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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