A Dominant Mutation in FBXO38 Causes Distal Spinal Muscular Atrophy with Calf Predominance
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- 作者：Charlotte聽J. Sumner ; Constantin d鈥橸dewalle ; Joe Wooley ; Katherine聽A. Fawcett ; Dena Hern ; ez ; Alice聽R. Gardiner ; Bernadett Kalmar ; Robert聽H. Baloh ; Michael Gonzalez ; Stephan Z眉chner ; Horia聽C. Stanescu ; Robert Kleta ; Ami Mankodi ; David聽R. Cornblath ; Kevin聽B. Boylan ; Mary聽M. Reilly ; Linda Greensmith ; Andrew聽B. Singleton ; Matthew聽B. Harms ; Alex ; er聽M. Rossor ; et al.
- 刊名：The American Journal of Human Genetics
- 出版年：7 November, 2013
- 年：2013
- 卷：93
- 期：5
- 页码：976-983
- 全文大小：869 K
文摘
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 Kr眉ppel-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聽motor neurons. Together, these results suggest that a transcriptional regulatory pathway that has a well-established role in聽axonal development could also be critical for neuronal maintenance and highlight the importance of FBXO38 and KLF7 activity in motor neurons.