Disease relevance of GDAP1

• We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21 [1].
• We investigated cell localization of GDAP1 in a human neuroblastoma cell line by means of transient overexpression and co-localization with organelle markers in COS-7 cells and by western blot analysis of subcell fractions with anti-GDAP1 polyclonal antibodies [2].
• Neurophysiology and nerve pathology were heterogeneous in these cases: a subset of GDAP1 mutations was associated with peripheral nerve demyelination, whereas others resulted in axonal degeneration [3].
• Patients with GDAP1 mutations displayed severe, early childhood-onset CMT neuropathy with prominent pes equinovarus deformity and impairment of hand muscles [3].
• Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene [4].

High impact information on GDAP1

• Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21 [5].
• 1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes [1].
• We previously localized and fine-mapped Charcot Marie Tooth 4A (CMT4A), the autosomal recessive, demyelinating peripheral neuropathy, to chromosome 8 [5].
• Overexpression of GDAP1 induces fragmentation of mitochondria without inducing apoptosis, affecting overall mitochondrial activity, or interfering with mitochondrial fusion [6].
• We show that neurons and Schwann cells express ganglioside-induced differentiation associated protein 1 (GDAP1), which suggest that both cell types may contribute to the mixed features of the disease [6].

Biological context of GDAP1

• Mutations in GDAP1 lead to severe forms of the peripheral motor and sensory neuropathy, Charcot-Marie-Tooth disease (CMT), which is characterized by heterogeneous phenotypes, including pronounced axonal damage and demyelination [6].
• GDAP1-specific knockdown by RNA interference results in a tubular mitochondrial morphology [6].
• The latter activity also is reduced strongly for disease-associated GDAP1 point mutations [6].
• We report four additional families with recessive mutations (487C-->T, Q163X; 359G-->A, R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the same haplotype suggesting a Spanish founder mutation [7].
• In this study, we identified two novel mutations disrupting the GDAP1 reading frame [3].

Anatomical context of GDAP1

• GDAP1 truncations that are found in patients who have CMT are not targeted to mitochondria and have lost mitochondrial fragmentation activity [6].
• Our data indicate that an exquisitely tight control of mitochondrial dynamics, regulated by GDAP1, is crucial for the proper function of myelinated peripheral nerves [6].
• One subgroup designated CMT4 type A (CMT4A) was selected from a series of Tunisian CMT4 families according to the following electrophysiological and pathological criteria: slow motor nerve conduction velocity (MCV), severe hypomyelination upon nerve biopsy with basal lamina onion bulbs and no myelin outfolding [8].
• Only in a few CMT4A affected patients sural nerve biopsy findings have been provided [9].

Associations of GDAP1 with chemical compounds

• The protein encoded by GDAP1 shows clear similarity to glutathione transferases (also known as glutathione S-transferases or GSTs) [10].
• Thus, GDAP derivatives provide versatile new tools for biologists to quantify and covalently capture minute quantities of glycans for exploring their structures and functions and generating new glycan arrays from naturally occurring glycans [11].

Other interactions of GDAP1

• The human genome contains a paralog of GDAP1 called GDAP1L1 [10].
• Traditionally, the different classes of CMT have been divided into demyelinating forms (CMT1, CMT3, and CMT4) and axonal forms (CMT2), a clinically very useful distinction [12].
• In GDAP1 and DNM2 mutants, both Schwann cells and axons/neurons might be directly affected [13].
• In addition, using SSCP and our physical map, we have demonstrated that the myelin protein PMP-2, mapped by FISH to this region, is not the defect in CMT4A [14].

Analytical, diagnostic and therapeutic context of GDAP1

• This axonal form of Charot-Marie-Tooth disease associated with a new GDAP1 mutation is recessively inherited and is characterized by a severe phenotype, since patients become wheelchair bound in the third decade, and present vocal cord and diaphram paralysis, which may be missed as they had no respiratory symptoms until the third decade [15].
• To further characterise their structure and function we purified recombinant human GDAP1 and GDAP1L1 proteins using bacterial expression and immobilised metal affinity chromatography [16].
• Ovariectomy downregulated expression of elongation factor-1alpha (3.5-fold), ganglioside-induced differentiation associated protein (8.2-fold), and NADH:ubiquinone oxidoreductase (3.8-fold) [17].

References