HGNC Approved Gene Symbol: GDAP1
SNOMEDCT: 715796006, 719512003, 725047007;
Cytogenetic location: 8q21.11 Genomic coordinates (GRCh38) : 8:74,350,403-74,488,872 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q21.11 | Charcot-Marie-Tooth disease, axonal, type 2K | 607831 | Autosomal dominant; Autosomal recessive | 3 |
| Charcot-Marie-Tooth disease, axonal, with vocal cord paresis | 607706 | Autosomal recessive | 3 | |
| Charcot-Marie-Tooth disease, recessive intermediate, A | 608340 | Autosomal recessive | 3 | |
| Charcot-Marie-Tooth disease, type 4A | 214400 | Autosomal recessive | 3 |
The GDAP1 gene encodes a protein expressed in the central and peripheral nervous system, particularly in Schwann cells. GDAP1 is an integral membrane protein of the outer mitochondrial membrane (Niemann et al., 2005).
Gangliosides, sialic acid-containing glycosphingolipids, are abundant in brain tissue, and GD3 synthase (SIAT8; 601123) plays a key role in their biosynthesis. Using differential display PCR to identify cDNAs induced at different time points by GD3 synthase expression in a mouse neuroblastoma cell line, Liu et al. (1999) obtained cDNAs encoding 10 Gdap proteins, including Gdap1. The deduced 358-amino acid human GDAP1 protein is 94% identical to the mouse protein, with most divergence at the N terminus. Northern blot analysis revealed expression of a 4.1-kb Gdap1 transcript restricted to mouse brain tissue. Immunofluorescence microscopy demonstrated cytoplasmic expression in mouse cells.
Pedrola et al. (2005) stated that GDAP1 contains 2 N-terminal GST domains and 2 C-terminal transmembrane domains. Real-time PCR of adult rat tissues detected highest expression in spinal cord, dorsal root ganglia, and brain, with low expression in sciatic nerve, and no expression in liver or muscle. GDAP1 localized to the mitochondria in a human neuroblastoma cell line and in COS-7 cells. Western blot analysis of subcellular fractions with anti-GDAP1 antibody detected a 40-kD band corresponding to GDAP1 and an 88-kD band, suggesting that GDAP1 forms a homodimer. The C-terminal transmembrane domains were necessary for correct localization in mitochondria; however, missense mutations did not alter mitochondrial localization.
Cuesta et al. (2002) determined that the GDAP1 gene contains 6 exons.
Xin et al. (2008) noted that the GDAP1 gene maps to chromosome 8q13.1-q21.1.
Gross (2013) mapped the GDAP1 gene to chromosome 8q21.11 based on an alignment of the GDAP1 sequence (GenBank BC024939) with the genomic sequence (GRCh37).
The GDAP1 gene may be involved in a signal transduction pathway in neuronal development. By Northern blot analysis, Cuesta et al. (2002) showed greatest GDAP1 expression in whole brain and spinal cord. Amplification of human sural nerve and mouse sciatic nerve transcripts suggested that GDAP1 expression does not occur just in neurons but also in Schwann cells. However, GDAP1 expression is higher in central tissues than in peripheral nerves.
Niemann et al. (2005) demonstrated that Gdap1 was expressed in both Schwann cells and neurons of rat peripheral nerve, as well as in various regions of the central nervous system. Subcellular localization studies showed that Gdap1 is an integral membrane protein of the outer mitochondrial membrane. Overexpression of Gdap1 induced fragmentation of mitochondria without inducing apoptosis, affecting overall mitochondrial activity, or interfering with mitochondrial fusion. The mitochondrial fusion proteins, mitofusin-1 (MFN1; 608506) and -2 (MFN2; 608507) and Drp1 (603850) were able to counterbalance these effects. Gdap1-specific knockdown by RNA interference resulted in a tubular mitochondrial morphology. Niemann et al. (2005) concluded that GDAP1 regulates mitochondrial dynamics that are critical for the proper function of myelinated peripheral nerves.
Pedrola et al. (2005) found that GST-activity assay detected no activity for soluble GDAP1. Shield et al. (2006) confirmed that the GDAP1 protein does not have glutathione transferase activity, although it appears to be structurally related to other cytosolic glutathione S-transferases (GST).
Homozygous or Compound Heterozygous GDAP1 Mutations
In 4 different Tunisian families with Charcot-Marie-Tooth disease type 4A (CMT4A; 214400), an autosomal recessive form of demyelinating peripheral neuropathy mapping to chromosome 8, Baxter et al. (2002) found homozygosity for 2 nonsense mutations and 1 missense mutation in the GDAP1 gene (W31X, 606598.0001; S194X, 606598.0002; R161H, 606598.0003).
In 3 Spanish families reported by Sevilla et al. (2001) with axonal Charcot-Marie-Tooth neuropathy and vocal cord paresis (607706), Cuesta et al. (2002) identified 3 distinct mutations in the GDAP1 gene (S194X; Q163X, 606598.0004; 863insA, 606598.0005). All mutations occurred in the homozygous or compound heterozygous state, consistent with autosomal recessive inheritance. Thus, mutations in GDAP1 can be associated with both axonal and demyelinating phenotypes, as reported for the myelin protein zero gene (MPZ; 159440) (Lewis et al., 2000; Vance, 2000).
Nelis et al. (2002) pointed out that the mutations in GDAP1 causing early-onset, severe autosomal recessive CMT show a range of nerve conduction velocities with some patients falling in the normal or near normal range, suggesting an axonal neuropathy, whereas others have severely slowed nerve conduction velocities compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show mixed or intermediate features of demyelination and axonal degeneration. In 7 families with autosomal recessive CMT compatible with linkage to the CMT4A locus at 8q21.1, Nelis et al. (2002) observed homozygosity for 3 distinct mutations in GDAP1 (e.g., R282C, 606598.0006).
In all 4 affected members of a consanguineous Moroccan family with severe axonal CMT (CMT2K; 607831), Birouk et al. (2003) identified homozygosity for the S194X mutation in the GDAP1 gene that had previously been identified in patients with CMT4A.
Niemann et al. (2005) showed that disease-associated GDAP1 truncation mutants (S194X and 863insA) were not targeted to the mitochondria and lost mitochondrial fragmentation activity, confirming that the C terminus is important for mitochondrial localization. Disease-associated GDAP1 missense mutants (R161H and R282C) were targeted to the mitochondria but showed some impairment in the ability to induce fragmentation compared to wildtype.
Heterozygous GDAP1 Mutations
In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal CMT (see 607831), Claramunt et al. (2005) identified a heterozygous mutation in the GDAP1 gene (R120W; 606598.0009). The patients had onset at the end of their second decade and very slow progression of the disorder, which was a milder phenotype than that seen in most patients carrying 2 GDAP1 mutations. Claramunt et al. (2005) noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations.
Chung et al. (2008) identified a heterozygous mutation in the GDAP1 gene (Q218E; 606598.0012) in a Korean father and daughter with autosomal dominant adult-onset axonal CMT2K (see 607831). The phenotype was milder than that usually observed in patients with recessive GDAP1 mutations.
Crimella et al. (2010) identified 3 different heterozygous mutations in the GDAP1 gene (see, e.g., R226S, 606598.0015) in 3 (27%) of 11 Italian probands with dominant inheritance of axonal CMT2K. Two of the mutations occurred in the GST domain, and 1 was a truncating mutation resulting in the elimination of the GST domain, suggesting that the GST domain is a frequent target of mutations for the dominant form of CMT2K.
Zimon et al. (2011) reported 8 unrelated families with autosomal dominant CMT due to 4 different heterozygous mutations in the GDAP1 gene (606598.0009; 606598.0017-606598.0019). The R120W was found in 3 unrelated families of Italian, Austrian, and Ashkenazi Jewish descent, respectively, and haplotype analysis indicated a founder effect. The phenotype varied considerably, even within a family, and some mutation carriers were asymptomatic, consistent with incomplete penetrance. The age at onset ranged from childhood to adulthood, and the most common initial symptom was walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, but most patients remained ambulatory. A few patients also developed proximal weakness. The majority of patients had an axonal pattern on electrophysiologic studies, but 2 unrelated patients with a more severe phenotype had an intermediate pattern between axonal and demyelinating. Zimon et al. (2011) noted that the phenotype in heterozygous GDAP1 mutation carriers was generally milder than that in patients with 2 mutations.
In 2 families with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; 214400), Baxter et al. (2002) found that affected individuals were homozygous for a c.92G-A transition in exon 1 of the GDAP1 gene that converted tryptophan-31 to a stop codon (W31X) and was predicted to result in a truncated protein. Affected individuals of the 2 families shared a haplotype surrounding the GDAP1 gene.
Charcot-Marie-Tooth Disease, Demyelinating, Type 4A
In a Tunisian family with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; 214400), Baxter et al. (2002) found that affected individuals were homozygous for a nonsense mutation in exon 5 of the GDAP1 gene, ser194 to stop (S194X), which was predicted to result in a truncated protein. This amino acid substitution was the result of a C-to-G transversion at nucleotide 581 (C581G). This family did not share any haplotype over the entire CMT4 region with any other Tunisian family with this disorder.
In a consanguineous family, Nelis et al. (2002) observed homozygosity for this mutation in 2 sisters with autosomal recessive CMT4A. They had onset at ages 2 months and 1 year with foot deformity and hammertoes as the initial symptoms, respectively. At least 1 of them had muscle weakness in both the lower limbs and upper limbs as well as sensory loss and absence of reflexes.
Charcot-Marie-Tooth Disease with Vocal Cord Paresis
Cuesta et al. (2002) found this mutation in compound heterozygosity with Q163X (606598.0004) in a small Spanish family with an axonal CMT phenotype associated with hoarse voice and vocal cord paresis (607706).
Charcot-Marie-Tooth Disease, Axonal, Type 2K
In all 4 affected members of a consanguineous Moroccan family with severe axonal CMT (CMT2K; 607831), Birouk et al. (2003) identified homozygosity for the S194X mutation in the GDAP1 gene. Vocal cord paresis was not present.
In a Tunisian family with demyelinating Charcot-Marie-Tooth disease type 4A (CMT4A; 214400), Baxter et al. (2002) found that affected members were homozygous for a c.482G-A transition in exon 3 of the GDAP1 gene, resulting in an arg161-to-his (R161H) substitution.
In a large inbred Spanish family with autosomal recessive distal axonal neuropathy with hoarseness and vocal cord paresis (607706), Cuesta et al. (2002) found that affected members were homoallelic for a gln163-to-stop (Q163X) mutation in the GDAP1 gene, caused by a C-to-T transition at nucleotide 487. In another smaller family, affected members were compound heterozygotes for the Q163X and S194X (606598.0002) mutations in the GDAP1 gene.
Boerkoel et al. (2003) identified homozygosity for the Q163X mutation in 5 patients from 3 unrelated Hispanic families with an early onset form of autosomal recessive CMT. Based on the finding of a common pathogenic haplotype among all patients, the authors suggested that the Q163X mutation is a founder mutation that may have arisen in Spain. Clinical features of these patients included onset at about the first year of life, with severe distal muscle weakness leading to disability in the second decade of life. One patient had vocal cord weakness. Nerve conduction velocities in 2 patients were consistent with axonal CMT. Histopathologic changes showed both demyelination and axonal loss, as well as onion bulb formations.
Claramunt et al. (2005) identified homozygosity for the Q163X mutation in affected probands from 4 unrelated families with axonal neuropathy and vocal cord paresis. All patients were of Spanish ancestry. Haplotype analysis indicated a founder effect originating in the Iberian peninsula approximately 33,000 years ago.
In a small family of Spanish ancestry, Cuesta et al. (2002) found that the index member affected by distal axonal neuropathy associated with hoarseness and vocal cord paresis (607706) was heteroallelic for a 1-bp insertion, c.863insA, in exon 6, leading to a frameshift mutation that generated 2 abnormal amino acids after threonine-288 and terminated the protein at codon 290 (T288fsX290). The 863insA mutation was found in compound heterozygous state with the Q163X mutation (606598.0004).
In 2 sisters (CMT-136.3 and CMT-136.4) with a mixed form of axonal and demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMTRIA; 608340) from a consanguineous Turkish family, Nelis et al. (2002) identified homozygosity for a c.844C-T change in the GDAP1 gene, resulting in an arg282-to-cys (R282C) substitution. The unaffected parents were heterozygous for the mutation.
In 2 affected members of a consanguineous Turkish family (AC531) with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; 608340), Senderek et al. (2003) identified homozygosity for a 1-bp insertion (c.349_350insT) in exon 3 of the GDAP1 gene, resulting in a premature stop codon.
In a German girl (family AC49) with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; 608340), Senderek et al. (2003) identified homozygosity for a splice site mutation in the GDAP1 gene (c.579+1G-A), predicted to result in the skipping of exon 4.
In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal Charcot-Marie-Tooth disease type 2K (CMT2K; 607831), Claramunt et al. (2005) identified a heterozygous c.358C-T transition in the GDAP1 gene, resulting in an arg120-to-trp (R120W) substitution in a conserved region of the protein. The patients had onset at the end of the second decade and very slow progression, which was a milder phenotype than that seen in most patients carrying 2 GDAP1 mutations. Claramunt et al. (2005) noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations.
Zimon et al. (2011) identified a heterozygous R120W substitution in affected members of 3 unrelated families with dominant inheritance of axonal CMT. The families were of Italian, Austrian, and Ashkenazi Jewish descent, respectively. Haplotype analysis indicated a common origin of the mutation, consistent with a founder effect. Expression of the R120W dominant mutation in HeLa cells resulted in impaired mitochondrial fusion, supporting its pathogenicity. The phenotype was considerably variable: age at onset ranged from childhood to adulthood. Walking difficulties were the most common initial symptom and the disorder was slowly progressive, but patients remained ambulatory with mainly distal muscle weakness and atrophy. Two patients also developed proximal weakness. One mutation carrier was asymptomatic, indicating incomplete penetrance.
For a discussion of a possible modifier effect on the GDPA1 R120W mutation by a R213P variant in the JPH1 gene, see 605266.0001.
In a sporadic case of severe Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Claramunt et al. (2005) identified a de novo heterozygous c.469A-C transversion in the GDAP1 gene, resulting in a thr157-to-pro (T157P) substitution. The patient had early onset of symptoms within the first year of life, moderately reduced distal strength in the lower limbs, absent tendon reflexes, and optic atrophy.
Charcot-Marie-Tooth Disease, Recessive Intermediate A
In a 39-year-old woman with recessive intermediate Charcot-Marie-Tooth disease (CMTRIA; 608340), Kabzinska et al. (2006) identified a homozygous c.715C-T transition in exon 6 of the GDAP1 gene, resulting in a leu239-to-phe (L239F) substitution. The patient had early onset of a motor and sensory neuropathy leading to severe disability in the third decade of life.
Charcot-Marie-Tooth Disease, Type 2K
Kabzinska et al. (2010) identified the L239F mutation, either in homozygous state or in compound heterozygous state with another pathogenic GDAP1 mutation (see, e.g., R282C; 606598.0006), in affected individuals from 4 families and in 2 individual patients, all with early-onset autosomal recessive CMT. Five of the families were Polish and 1 was Bulgarian. The age at onset ranged from 2 to 10 years, and all had gait abnormalities due to lower limb weakness and atrophy. Two patients who were homozygous for the L239F mutation became wheelchair-bound as young adults. Electrophysiologic studies showed that most patients had normal motor and sensory nerve conduction velocities, whereas a few had reduced responses. The diagnosis was autosomal recessive sensorimotor axonal neuropathy (CMT2K; 607831). Haplotype analysis indicated a founder effect for the L239F mutation, indicating that it is prevalent in the Central and Eastern European populations. Kabzinska et al. (2010) observed that the phenotype resulting from this missense mutation was slightly milder than that associated with GDAP1 nonsense mutations (e.g., S194X; 606598.0002).
In a Korean father and daughter with late-onset autosomal dominant axonal Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Chung et al. (2008) identified a heterozygous c.652C-G transversion in the GDAP1 gene, resulting in a gln218-to-glu (Q218E) substitution in a highly conserved region of the glutathione S-transferase core region of the protein. The mutation was not identified in 374 control chromosomes. The patients had onset of gait difficulties at age 25 and 16 years, respectively. Other features included hand muscle atrophy, decreased distal sensation in the upper and lower limbs, and normal or mildly reduced nerve conduction velocities. Sural nerve biopsy findings in the father were consistent with a primarily axonal process, but there were also signs of demyelination. The phenotype in this family was much milder than that observed in patients with recessive GDAP1 mutations.
In 3 sibs from a consanguineous Amish family with autosomal recessive axonal Charcot-Marie-Tooth disease type 2K (CMT2K; 607831), Xin et al. (2008) identified a homozygous c.692C-T transition in exon 5 of the GDAP1 gene, resulting in a pro231-to-leu (P231L) substitution. The patients had childhood onset of distal lower muscle weakness and borderline nerve conduction velocity measurements, consistent with an axonal neuropathy. The disorder was gradually progressive with worsening of the lower limb symptoms, but the patients were still able to do some daily activities in their twenties. There was no vocal cord or hand muscle involvement. The variant was not seen in 100 control chromosomes from a Lancaster County Amish settlement, but was observed in heterozygosity in 7 (14%) of 50 control individuals from a Geauga County Amish settlement.
In 4 affected members of a French family with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Cassereau et al. (2009) identified a heterozygous c.719G-A transition in the GDAP1 gene, resulting in a cys240-to-tyr (C240Y) substitution in a conserved residue of the putative GST core region. Mitochondrial respiratory chain complex I activity in patient fibroblasts was 50% lower than controls, but the overall efficiency of ATP production was not affected, indicating compensatory mechanisms. Electron microscopy showed that the tubular mitochondria were 33% larger in diameter and that the mitochondrial mass was 20% greater compared to controls. Cassereau et al. (2009) concluded that, in addition to the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume. The authors postulated a dominant-negative effect of the C240Y mutation.
In an Italian mother and daughter child with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Crimella et al. (2010) identified a heterozygous c.678A-T transversion in exon 5 of the GDAP1 gene, resulting in an arg226-to-ser (R226S) substitution in a highly conserved region in the GST domain. The 25-year-old daughter presented with lower limb involvement at age 8 years and retained independent ambulation. The 49-year-old mother had EMG findings of axonal CMT at age 35 years but showed no clinical signs of the disorder. She developed mild lower limb involvement in her late forties. The mutation was not found in 500 controls. The family illustrated significant intrafamilial variability.
In 2 sisters from a small village in northeast Poland with a mixed form of axonal and demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMTRIA; 608340), Kabzinska et al. (2011) identified a homozygous c.980G-A transition in the GDAP1 gene, resulting in a gly327-to-asp (G327D) substitution in the transmembrane domain, which is important for targeting to the mitochondrial outer membrane. In vitro functional expression studies showed that the mutation interfered with mitochondrial targeting and insertion into the mitochondrial membrane. Cells with overexpression of GDAP1 had a predominantly fragmented mitochondrial morphology, consistent with its role as a mitochondrial fission factor. Cells expressing the G327D mutant protein showed no change in mitochondrial morphology compared to controls, indicating a complete loss of normal fission activity. Kabzinska et al. (2011) commented that this missense GDAP1 mutation resulted in a severe phenotype usually associated with nonsense mutations, and that the complete loss of fission activity on a cellular level correlates with a severe phenotype.
In affected members of 2 distantly related Polish families with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; 607831), Zimon et al. (2011) identified a heterozygous c.467C-G transversion in the GDAP1 gene, resulting in an ala156-to-gly (A156G) substitution at a highly conserved residue. One unaffected family member carried the mutation, consistent with incomplete penetrance. The mutation was not found in 280 control individuals. Expression of this dominant mutation in HeLa cells resulted in impaired mitochondrial fusion, caused mitochondrial fragmentation, and increased cell sensitivity to apoptosis. The patients had onset in the first or second decades of walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, and all patients remained ambulatory. Nerve conduction velocities showed an axonal pattern.
In 3 affected members of a large Finnish family with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Zimon et al. (2011) identified a heterozygous c.358A-G transition in the GDAP1 gene, resulting in a his123-to-arg (H123R) substitution. (The nucleotide numbering was based on a revised transcript.) Four older asymptomatic family members also carried the mutation, indicating incomplete penetrance. The mutation was not found in 280 control individuals. The phenotype was variable, with onset of difficulty walking due to distal muscle weakness and atrophy between 3 and 32 years of age. The disorder was slowly progressive, and all patients remained ambulatory. One patient had proximal weakness. Nerve conduction studies showed an axonal pattern. A heterozygous H123R mutation occurred de novo in a patient of Tunisian origin who was more severely affected and showed delayed motor development; that patient had intermediate results on electrophysiologic studies.
In an Italian father and son with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Zimon et al. (2011) identified a heterozygous c.821C-T transition in the GDAP1 gene, resulting in a pro274-to-leu (P274L) substitution at a highly conserved residue in the C-terminal GST domain. The mutation was not found in 280 control individuals. The father, who had onset of distal muscle weakness and atrophy at age 47 years and became wheelchair-bound at age 61, had an intermediate pattern on nerve conduction studies. The son was clinically asymptomatic, but showed an axonal pattern on nerve conduction studies.
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