SBF2 – Charcot-Marie-Tooth disease type 4B2

SBF2 encodes a pseudophosphatase member of the myotubularin family and is implicated in autosomal recessive Charcot-Marie-Tooth disease type 4B2 (MONDO:0011475) characterized by early-onset sensorimotor neuropathy. A multi-center study reported biallelic SBF2 mutations in seven unrelated families, identifying nine distinct private variants including exon deletions, de novo events, splice site changes, and frameshifts, all predicted to truncate or shorten the protein (PMID:30028002).

The inheritance mode is autosomal recessive, with neuropathy manifesting in the first decade after normal early motor milestones. Electrophysiological evaluation and nerve biopsies uniformly demonstrated demyelination and characteristic myelin outfoldings. Penetrance exceeded 90% by age ten, although glaucoma developed variably, underscoring the need for ophthalmic surveillance even in the absence of early ocular findings (PMID:30028002; PMID:35562614).

Variant spectrum comprises nine loss-of-function alleles, including small deletions (c.765_770del (p.Pro256_Ile257del)), splice site disruptions, and larger exon-level deletions. Recurrent or founder mutations have not been observed; all alleles remain private to individual families. The one reported Turkish proband with c.765_770del (p.Pro256_Ile257del) further extends the allelic series (PMID:35562614).

Functional studies of the murine Sbf2 orthologue reveal an ~8 kb transcript encoded by 40 exons, with broad tissue expression and cytoplasmic localization of the protein. Disease-associated mutations uniformly lead to truncated proteins, implicating a loss-of-function mechanism. However, no in vivo phenotypic modeling or rescue experiments have been reported to date (PMID:16750429).

No studies to date dispute the role of SBF2 in CMT4B2. The collective genetic evidence from multiple families, coupled with consistent functional data supporting haploinsufficiency, establishes a moderate level of clinical validity. Comprehensive mutation scanning is warranted in early-onset demyelinating neuropathy, even without ocular involvement.

Key Take-home: Biallelic loss-of-function variants in SBF2 cause autosomal recessive CMT4B2 with high penetrance, demyelination, and characteristic myelin outfoldings, supporting its clinical utility in genetic diagnosis and management.

References

• Clinical genetics • 2018 • Novel SBF2 mutations and clinical spectrum of Charcot-Marie-Tooth neuropathy type 4B2. PMID:30028002
• Gene expression patterns : GEP • 2006 • Cloning, expression and characterization of the murine orthologue of SBF2, the gene mutated in Charcot-Marie-Tooth disease type 4B2. PMID:16750429
• Neurogenetics • 2022 • Molecular characterization of Turkish patients with demyelinating Charcot-Marie-Tooth disease. PMID:35562614

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