title: A dominant mutation in FBXO38 causes distal spinal muscular atrophy with calf predominance.
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.
authors.affiliation: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address: csumner1@jhmi.edu.
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
authors.forename: Constantin
authors.initials: C
authors.lastname: d'Ydewalle
authors.forename: Joe
authors.initials: J
authors.lastname: Wooley
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fawcett
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Alice R
authors.initials: AR
authors.lastname: Gardiner
authors.forename: Bernadett
authors.initials: B
authors.lastname: Kalmar
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Horia C
authors.initials: HC
authors.lastname: Stanescu
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Ami
authors.initials: A
authors.lastname: Mankodi
authors.forename: David R
authors.initials: DR
authors.lastname: Cornblath
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Rossor
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000870:Anterior Horn Cells / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000378:metabolism / Q000473:pathology; D059472:Exome; D044783:F-Box Proteins / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D008040:Genetic Linkage; D057809:HEK293 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D055815:Young Adult
chemical_list: D044783:F-Box Proteins; C480503:KLF7 protein, human; D051741:Kruppel-Like Transcription Factors