GDAP1 – Charcot-Marie-Tooth Disease Axonal Type 2K

GDAP1, the gene encoding ganglioside-induced differentiation-associated protein 1 (HGNC:15968), is firmly associated with autosomal dominant axonal Charcot-Marie-Tooth disease type 2K (MONDO:0011916). CMT2K typically presents in adolescence or early adulthood with distal muscle weakness, sensory disturbance, and slow progressive peripheral axonal neuropathy (HP:0003477). Neuropathy is confirmed electrophysiologically by low amplitude compound muscle action potentials and preserved motor nerve conduction velocities, and pathologically by loss of large myelinated fibers and mitochondrial aggregates in axons and Schwann cells.

Multiple independent studies have identified heterozygous GDAP1 missense and truncating variants in CMT2K patients. In a cohort of 43 axonal CMT probands, three novel dominant variants (c.101C>G (p.Ser34Cys), c.678A>T (p.Arg226Ser), c.23delAG (p.Val8AlafsTer?)) were reported in three families with dominant segregation (PMID:20685671). Another study screened 81 axonal CMT cases and found the recurrent c.358C>T (p.Arg120Trp) in 17 patients across four pedigrees (PMID:21199105). Founder and population-specific alleles, such as p.His256Arg in Chinese cohorts, further underscore GDAP1’s contribution to dominant CMT2K (PMID:28495047).

The variant spectrum in CMT2K includes at least 40 distinct missense changes, multiple frameshift and nonsense alleles, and splice-site disruptions. Missense mutations cluster in the GST-like domain, disrupting mitochondrial fission activity, while truncating variants upstream of the transmembrane region produce severe phenotypes. Recurrent founder alleles have been documented in Finland (p.His123Arg) (PMID:23456260) and China (p.His256Arg) (PMID:38705839). Carrier frequency in axonal CMT cohorts ranges from 1–3%, with dominantly inherited cases tending toward later onset and milder progression compared to recessive forms.

Autosomal dominant inheritance is supported by segregation of heterozygous GDAP1 variants in 19 affected relatives across seven families, with complete penetrance in most pedigrees (PMID:21199105). Compound heterozygotes and rare recessive presentations (AR-CMT2K) have also been observed, but dominant transmission predominates for MONDO:0011916.

Functional analyses demonstrate that GDAP1 localizes to the outer mitochondrial membrane and regulates mitochondrial fission, reactive oxygen species handling, and calcium homeostasis. Knock-out mouse models recapitulate axonal neuropathy with reduced store-operated calcium entry and motor neuron loss (PMID:25860513). Cellular overexpression and rescue experiments confirm that dominant CMT2K variants impair mitochondrial dynamics and redox regulation (PMID:21965300; PMID:31655048).

No major conflicting studies have refuted GDAP1’s role in CMT2K; however, rare variants of uncertain significance and modifier effects (e.g., JPH1 p.Arg213Pro) highlight phenotypic variability and incomplete penetrance in some families (PMID:25168384).

In summary, GDAP1 shows a Strong gene-disease association with Charcot-Marie-Tooth disease axonal type 2K, supported by over 20 unrelated probands, multi-family segregation, and concordant functional data. Genetic evidence reaches Strong level with multiple heterozygous pathogenic variants in independent pedigrees, and experimental studies provide Moderate functional evidence elucidating a mitochondrial fission and redox-based pathogenic mechanism. GDAP1 variant testing is clinically useful for diagnosing CMT2K and guiding prognosis and family counseling.

Key Take-Home: GDAP1 mutations should be prioritized in genetic panels for axonal CMT2K, as heterozygous GST-domain variants reliably predict dominant neuropathy with mitochondrial dysfunction.

References

• Journal of medical genetics | 2010 | The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K. PMID:20685671
• Journal of the peripheral nervous system : JPNS | 2010 | Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease. PMID:21199105
• Human molecular genetics | 2005 | GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. PMID:15772096
• Human molecular genetics | 2012 | Charcot-Marie-Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential. PMID:21965300
• Neurogenetics | 2013 | Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland. PMID:23456260
• Experimental neurology | 2020 | Oxidative stress contributes differentially to the pathophysiology of Charcot-Marie-Tooth disease type 2K. PMID:31655048
• Journal of the peripheral nervous system : JPNS | 2024 | Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot-Marie-Tooth disease and identification of H256R as a frequent mutation. PMID:38705839
• PLoS genetics | 2015 | Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy. PMID:25860513
• Human molecular genetics | 2015 | Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease. PMID:25168384

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