FBXO38 was first reported in relation to autosomal dominant distal hereditary motor neuropathy (dHMN) in 2013 (Sumner et al., PMID: 24207122). dHMN, with variable age of onset and severity, presents with primary features of calf weakness and slowly progressive weakness of both distal and proximal leg and arm muscles. FBXO38, F-Box only protein 38, is expressed in the human brain, spinal cord, and skeletal muscle. The function is hypothesized to include 1) ubiquitination, through acting as a subunit of the SCF (Skp1-cullin-Fbox) E3 ubiquitin ligase complex and 2) as a transcription factor by acting as a coactivator of Kruppel-like factor 7 (KLF7), a member of the KLF family of zinc finger transcription factors, that plays critical roles in axonal outgrowth and regeneration. The mechanism of pathogenicity is not yet established but at least one report suggested loss of function. Two variants, reported in 3 probands in 2 publications (PMIDs: 24207122, 34103343), are included in this curation. The first variant was identified in a large family with 4+ generations of affected individuals. Extensive segregation data was collected, which was consistent with gene-disease association (15 affected individuals tested positive, 24 unaffected individuals tested negative, no conflicting evidence). This variant was then found in an additional unrelated proband and their similarly affected parent. A second variant was identified in an individual with juvenile-onset upper limb distal weakness. Both variants are located in a highly conserved nuclear export signal region. Of note, a homozygous variant was reported in a consanguineous individual with early onset slowly progressive distal motor neuronopathy accompanied by hearing loss and multiple organ anomalies; heterozygous parents and a maternal aunt were asymptomatic (PMID: 31420593). This publication was not included in this curation due to lack of functional evidence. The disease-gene association appears to be moderate with the combined genetic and experimental evidence indicating a score of 9.5 for FBXO38 and autosomal dominant distal hereditary motor neuropathy.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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