The linkage region of SBF2 on chromosome 11p15 was first reported in 1999 in association with autosomal recessive CMT with focally-folded myelin (PMID: 10644431). In 2003, an in-frame deletion in SBF2 was described (PMID: 12554688), followed by several stop (e.g. 12687498, 15304601), frame-shift (PMID: 25873783, 30028002), and splice variants (PMID: 15477569) all representing biallelic loss-of-function changes. The mutation spectrum was later enlarged by missense variants as well (PMID: 30028002), likewise leading to a childhood-onset CMT phenotype with slow nerve conduction velocities (~ 15m/s) and tomaculous myelin outfoldings. The loss-of function pathomechanism is supported by a SBF2 knockout mouse model (PMID: 17855448, 18349142, 23297362) well-reproducing phenotypic elements such as muscle weakness, poor motor performance, reduced nerve conduction velocities and delayed F-waves, as well as myelin folding abnormalities. SBF2 is expressed in the Schwann cell cytoplasm (PMID: 23297362) and interacts with MTMR2 (15998640, 23297362), a protein that is likewise associated with AR demyelinating CMT (CMT4B1). In summary, SBF2 is definitively associated with autosomal recessive demyelinating Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.
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