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FRABIN, encoded by the FGD4 gene, is a Rho GDP/GTP exchange factor critical for Schwann cell myelination. Biallelic loss-of-function variants in FGD4 cause CMT4H, an autosomal recessive demyelinating neuropathy, and contribute to the broader phenotype of Charcot-Marie-Tooth disease ([MONDO:0015626]). The clinical presentation includes early-onset sensorimotor neuropathy with slowed nerve conduction velocities, foot deformities, kyphoscoliosis, and myelin outfoldings on nerve biopsy.
Pathogenic FGD4 alleles have been reported in at least 13 probands from six unrelated consanguineous or AR-inherited families ([PMID:19221294]; [PMID:23550889]; [PMID:23466821]; [PMID:34169998]; [PMID:31852984]; [PMID:31152969]; [PMID:19332693]). Segregation analysis in multiple pedigrees confirms autosomal recessive inheritance, with homozygous or compound heterozygous variants co-segregating with disease in affected siblings. Functional concordance is supported by Schwann cell-specific knockout models and rescue experiments that reproduce and ameliorate hypermyelination, respectively.
Case reports include a Northern Irish family with a homozygous truncating variant c.1234C>T (p.Arg412Ter) leading to a slowly progressive demyelinating neuropathy in two adults remaining ambulant into middle age ([PMID:19221294]). Tunisian siblings harboring c.514_515insG (p.Asn172ArgfsTer3) presented with severe early-onset CMT4H and kyphoscoliosis ([PMID:23550889]). A Japanese cohort identified three AR cases with splice-site and frameshift mutations, including c.1248-2A>G and c.2301_2305del (p.Lys767fs) in 103 demyelinating CMT patients ([PMID:23466821]). Additional FGD4 pathogenic variants have been described in isolated and panel-diagnosed cases, as well as copy number deletions ([PMID:34169998]; [PMID:31852984]; [PMID:31152969]; [PMID:19332693]).
The variant spectrum is dominated by loss-of-function alleles: five nonsense or frameshift mutations (e.g., p.Arg412Ter; p.Ala172ArgfsTer3) and four splice-site or CNV events, consistent with haploinsufficiency as the pathogenic mechanism. Recurrent mutations have not been observed, reflecting a diverse allelic heterogeneity across populations. Carrier frequency is low, but FGD4 screening is recommended in early-onset demyelinating CMT, especially in consanguineous families.
Functional studies using Fgd4SC–/– conditional knockout mice demonstrate Schwann cell–intrinsic roles for FRABIN in regulating NRG1 type III/ERBB2/3 signaling and endocytic trafficking, leading to focal hypermyelination and myelin outfoldings in vitro and in vivo ([PMID:36314052]). Rescue of myelin pathology by niacin treatment highlights a potential therapeutic strategy and underscores the relevance of disrupted ERBB2/3 trafficking in CMT4H pathophysiology.
No conflicting evidence has been reported disputing FGD4’s role in AR demyelinating CMT. Overall, multiple independent AR cases, robust segregation, and concordant mechanistic data establish a strong gene-disease relationship between FGD4 and Charcot-Marie-Tooth disease.
Key Take-home: Biallelic loss-of-function variants in FGD4 cause autosomal recessive demyelinating Charcot-Marie-Tooth disease with a characteristic hypermyelination phenotype, supporting precise genetic diagnosis and informing emerging therapeutic approaches.
Gene–Disease AssociationStrong13 probands across 6 unrelated AR families; segregation in multiple consanguineous pedigrees; concordant functional data (knockout mouse model and rescue experiments) Genetic EvidenceStrong13 probands with biallelic FGD4 variants across 6 families, including 9 loss-of-function alleles Functional EvidenceModerateSchwann cell-specific knockout and niacin rescue experiments demonstrate mechanistic concordance with human phenotype |