GDAP1 – Charcot-Marie-Tooth disease type 4A

GDAP1 (ganglioside-induced differentiation-associated protein 1) is causally linked to autosomal recessive Charcot-Marie-Tooth disease type 4A (CMT4A) through loss-of-function and missense variants. A hallmark of CMT4A is early-onset severe sensorimotor neuropathy with mixed demyelinating and axonal pathology. The mode of inheritance is autosomal recessive, with complete co-segregation of pathogenic GDAP1 variants in affected families.

Initial genetic evidence arose from screening of seven unrelated AR CMT4A families (seven probands) revealing a nonsense c.581C>G (p.Ser194Ter), a frameshift c.786delG (p.Phe263LeufsTer22) and a missense c.844C>T (p.Arg282Cys) in GDAP1 ([PMID:12499475]). Subsequent studies identified four additional AR CMT4A families carrying c.487C>T (p.Gln163Ter), a Hispanic founder allele present on a common haplotype ([PMID:12601710]), and three Italian families with c.347T>G (p.Met116Arg) as a founder variant ([PMID:15377708]). In total, 14 unrelated AR CMT4A families support a definitive gene-disease association.

The variant spectrum in CMT4A includes at least six truncating alleles (nonsense and frameshift), recurrent founder alleles (p.Gln163Ter in Hispanics), and multiple missense changes affecting conserved residues. Functional assays demonstrate that GDAP1 localizes to the outer mitochondrial membrane and is highly expressed in neurons versus Schwann cells, implicating mitochondrial dynamics in disease pathogenesis ([PMID:15772096]).

In vivo, Gdap1 knockout mice develop progressive axonal neuropathy with motor impairment, reduced store-operated Ca2+ entry and abnormal mitochondrial morphology in motor neurons ([PMID:25860513]). Studies in patient fibroblasts also reveal reduced mitochondrial membrane potential and altered glutathione homeostasis, further linking GDAP1 dysfunction to oxidative stress and neurodegeneration.

No credible conflicting evidence has been reported. Overall, genetic and functional data meet ClinGen criteria for a Definitive association between GDAP1 and CMT4A. Key take-home: GDAP1 variant screening enables molecular diagnosis of early-onset AR CMT4A and guides genetic counseling and emerging mitochondrial-targeted therapies.

References

• Neurology • 2002 • Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. PMID:12499475
• Annals of neurology • 2003 • CMT4A: identification of a Hispanic GDAP1 founder mutation. PMID:12601710
• Journal of neurology, neurosurgery, and psychiatry • 2004 • A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect. PMID:15377708
• 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
• PLoS genetics • 2015 • Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy. PMID:25860513

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