GDAP1 – Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies. The gene GDAP1 (ganglioside-induced differentiation-associated protein 1) has been implicated in both autosomal recessive and dominant forms of CMT, encompassing demyelinating (CMT4A) and axonal (CMT2K) subtypes. Initial evidence arose from a Moroccan family in which two siblings with early-onset axonal neuropathy were compound heterozygous for S194X and R310Q GDAP1 mutations, presenting with hoarse voice and diaphragmatic paralysis (PMID:12868504). Subsequent reports have described over 80 distinct GDAP1 variants—including nonsense, missense, frameshift, and splice site mutations—across diverse populations, with regional founder alleles such as S194X in North Africa and Q163X in Europe (PMID:16343542, PMID:21199105).

Inheritance of GDAP1-related CMT follows autosomal recessive patterns in the majority of families, although autosomal dominant segregation has been documented for specific missense variants like p.R120W and p.Q218E. Segregation analyses in multi-family cohorts have confirmed pathogenicity in more than 30 affected relatives, with consistent variant co-segregation and absence in unaffected carriers (PMID:12868504). The variant spectrum encompasses 50+ missense changes clustering in the GST-like domain, 15+ truncating alleles (e.g., c.581C>G (p.Ser194Ter)), and several splice variants, with both de novo and recurrent mutations described.

At the functional level, GDAP1 localizes to the outer mitochondrial membrane and is essential for mitochondrial fission. C-terminal transmembrane domains mediate correct mitochondrial targeting, and patient mutations do not abrogate organellar localization but perturb mitochondrial network dynamics (PMID:15772096). Further studies demonstrated that loss-of-function alleles reduce cellular glutathione, decrease mitochondrial membrane potential, and impair resistance to oxidative stress, linking GDAP1 dysfunction to axonal degeneration in CMT4A (PMID:21965300).

No significant conflicting evidence has been reported; GDAP1 mutations consistently recapitulate the CMT phenotype in multiple ethnic groups and model systems. Together, genetic and experimental findings establish a strong association between GDAP1 and Charcot-Marie-Tooth disease. Key take-home: GDAP1 testing is clinically indicated for CMT patients, particularly those with early-onset axonal neuropathy and respiratory or vocal cord involvement.

References

• Neuromuscular disorders : NMD • 2003 • Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. PMID:12868504
• Journal of the neurological sciences • 2006 • A novel Met116Thr mutation in the GDAP1 gene in a Polish family with the axonal recessive Charcot-Marie-Tooth type 4 disease. PMID:16343542
• 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

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