The gene SBF1 (set-binding factor 1), located at position 22q13.33, encodes a myotubularin-related protein (MTMR5) that is responsible for the subcellular localization of MTMR2, which is likewise CMT-associated. Structurally, it resembles SBF2/MTMR13. Together, all three MTMR proteins have been associated with autosomal recessive, demyelinating CMT with myelin outfoldings (CMT4). With the according phenotype, SBF1 was first identified by whole-exome-sequencing in three affected Korean individuals, who carried two missense variants in compound-heterozygosity (PMID: 23749797). Since then, however, no further family has been described carrying SBF1 mutations in association with CMT4B3. In contrast, five families (PMIDs: 24799518, 28005197, 32444983, 20658556, 30039846) of Saudi Arabian, Syrian, Isrealian, Spanish, and British descent have been identified with an axonal motor predominant neuropathy and cranial nerve involvement, including facial and ophthalmoparesis. As an imaging correlate, some of these patients showed T2-hyperintensities in pons and mesencephalon, called “fork and bracket” sign. Additional features repeatedly found in these families were spasticity, syndactyly, short stature, and intellectual disability. All affected individuals carried homozygous or compound-heterozygous variants in SBF1, including missense, splice, and frameshift mutations. We additionally reported another, yet unpublished case from US American Origin, matching this genotype-phenotype pattern. SBF1 is expressed in sural nerves (PMID: 23749797). Its interaction with MTMR2 has been shown by co-immunoprecipitation and confocal microscopy (PMID: 12668758). Unlike SBF2, SBF1-/- mice do not reproduce the clinical CMT phenotype (PMID: 11994405), but shown by electron microscopy, they seem to have a disturbed sorting of peripheral axon bundles (Mammel et al., 2019, evidence not scored). In summary, our score system suggests to classify the gene-disease relationship between SBF1 and autosomal recessive axonal neuropathy with cranial nerve involvement as MODERATE. This is mostly supported by genetic/clinical evidence and has been upheld over time, however, functional data on the underlying pathophysiology is lacking. The identification of more cases will most likely shift this classification towards “definitive” in the future. Evidence is insufficient to support or refute an association with demyelinating CMT4B.
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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