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 (m>FBXO38m>). 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 m>FBXO38m> 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.