Alternative titles; symbols
HGNC Approved Gene Symbol: GJC2
SNOMEDCT: 870287007;
Cytogenetic location: 1q42.13 Genomic coordinates (GRCh38) : 1:228,149,930-228,159,826 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q42.13 | ?Spastic paraplegia 44, autosomal recessive | 613206 | Autosomal recessive | 3 |
| Leukodystrophy, hypomyelinating, 2 | 608804 | Autosomal recessive | 3 | |
| Lymphatic malformation 3 | 613480 | Autosomal dominant | 3 |
The complete coding sequence of the GJA12 (GJC2) gene has been deposited in GenBank (AF014643). The GJA12 sequence encodes a 436-amino acid protein (GenBank AAB94511).
Orthmann-Murphy et al. (2007) noted that the GJC2 gene has 2 potential ATG start codons: 1 is located in the 5-prime untranslated region and is 9 nucleotides upstream of the ATG conventionally considered to be the connexin start codon. The protein was found to be expressed on primate oligodendrocytes.
For background information on connexins, see CX26 (GJB2; 121011).
Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. They have been identified in a broad range of mammalian tissues, and most tissues expressed more than 1 species of connexin protein. Menichella et al. (2003) found that Cx47 (Gja12) is expressed specifically in oligodendrocytes and that its expression is regulated in parallel with other myelin genes. Cx47 and Cx32 (Gjb1; 304040) partially colocalized in oligodendrocytes, which together with Schwann cells synthesize the multilamellar myelin membranes surrounding axons.
By RT-PCR analysis, Uhlenberg et al. (2004) examined the expression of GJA12 in comparison with that of GJB1. Both were more highly expressed in brain and spinal cord than in peripheral nerve tissue. GJA12 could be amplified from sciatic and sural nerves of healthy adults.
Uhlenberg et al. (2004) remarked that GJA12 seems to be more important for oligodendrocyte homeostasis than GJB1, which is mutant in X-linked Charcot-Marie-Tooth disease (CMTX1; 302800).
The GJA12 gene consists of a single exon (Uhlenberg et al., 2004).
The GJA12 gene maps to chromosome 1q41-q42 (Uhlenberg et al., 2004).
Gross (2014) mapped the GJC2 gene to chromosome 1q42.13 based on an alignment of the GJC2 sequence (GenBank AF014643) with the genomic sequence (GRCh37).
Hypomyelinating Leukodystrophy 2
In a consanguineous Turkish family and 2 nonconsanguineous German families with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804), also designated PMLD1, Uhlenberg et al. (2004) identified 5 different GJA12 mutations; they could not find GJA12 mutations in 3 other affected families. As expected, patients from the consanguineous family displayed a homozygous mutation, 857T-C (608803.0001). The 2 German families showed compound heterozygous GJA12 mutations. Some patients showed reduced nerve conduction velocities, which indicated the presence of a mild peripheral demyelinating motor neuropathy, predominantly of the lower limbs, consistent with GJA12 expression in sural and sciatic nerve tissue. Since Gjb1 and Gja12 are functionally redundant in mice, Uhlenberg et al. (2004) favored the hypothesis that the missense mutants of GJA12 found in their patients with Pelizaeus-Merzbacher-like disease (PMLD) displayed toxic gain of function in oligodendrocytes. Orthmann-Murphy et al. (2007) stated that the alternative ATG start codon used by Uhlenberg et al. (2004) is unlikely to be the initiation codon. Thus, the mutations described by Uhlenberg et al. (2004) contain 3 additional amino acids.
Wolf et al. (2007) identified a homozygous deletion in the GJA12 gene (608803.0006) in 2 sibs with hypomyelinating leukodystrophy who were born of consanguineous Pakistani parents.
Henneke et al. (2008) identified 11 mutations (see, e.g., 608803.0007) in the GJA12 gene in affected members of 14 (7.7%) of 182 families with a PMLD-like phenotype. The authors concluded that GJA12 mutations are not a common cause for a PMLD-like disorder.
Diekmann et al. (2010) investigated the in vitro functional effects of 4 different PMLD-like GJC2 mutations in HeLa cells and oligodendrocyte precursors. The mutants thr265-to-ala (T265A) and a complex mutation (A98G_V99insT) were retained in the endoplasmic reticulum (ER), gly149-to-ser (G149S) localized to both the ER and the plasma membrane, and thr398-to-ile (T398I )formed gap junctional plaques at the plasma membrane. Voltage clamp studies showed significantly decreased hemichannel currents for gly236-to-arg (G236R), T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wildtype, but these channels were dysfunctional under depolarization activation conditions. The findings indicated that PMLD is most often caused by a loss of function, but that channel dysfunction may also occur.
Spastic Paraplegia 44
In 3 affected members of an Italian family with hereditary spastic paraplegia-44 (SPG44; 613206), Orthmann-Murphy et al. (2009) identified a homozygous mutation in the GJC2 gene (I33M; 608803.0008). Heterozygous family members were unaffected. The authors noted that the phenotype was less severe than hypomyelinating leukoencephalopathy-2 (HLD2; 608804), an allelic disorder.
Lymphatic Malformation 3
In affected members of 2 large families with autosomal dominant lymphatic malformation-3 (LMPHM3; 613480), Ferrell et al. (2010) identified 2 different heterozygous mutations in the GJC2 gene (608803.0009 and 608803.0010, respectively). Both mutations affected the extracellular domain. Affected individuals had onset in the first or second decade of uncomplicated lymphedema of the lower limbs, and some later developed upper limb involvement. Incomplete penetrance was observed. Ferrell et al. (2010) hypothesized that the mutations may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow. Four additional putative mutations in the GJC2 gene were identified in 4 smaller families with lymphedema; no functional studies were performed.
By linkage analysis followed by whole-exome sequencing, Ostergaard et al. (2011) identified a heterozygous mutation in the GJC2 gene (S48L; 608803.0009) in 8 affected members of a family with autosomal dominant primary lymphedema. Genetic analysis of an unrelated affected family identified the same pathogenic mutation. Further sequencing of this gene in 19 unrelated individuals with lymphedema identified 3 with mutations in the GJC2 gene, 2 of whom also carried the S48L substitution. Ostergaard et al. (2011) concluded that mutations in GJC2 are a significant cause of autosomal dominant primary lymphedema.
Gja12 knockout mice are completely Gja12-deficient but clinically normal (Odermatt et al., 2003). Mice lacking both Cx47 and Cx32 (Gjb1) develop severe oligodendrocyte death and present with tremor and tonic seizures (Odermatt et al., 2003; Menichella et al., 2003). By electron microscopy, Odermatt et al. (2003) observed conspicuous vacuolation of nerve fibers in central nervous system white matter of Cx47-deficient mice, particularly at the site of the optic nerve where axons are first contacted by oligodendrocytes and myelination starts.
In a consanguineous Turkish family, Uhlenberg et al. (2004) found that members with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) were homozygous for a T-to-C transition at cDNA position 857 of the GJA12 gene that was predicted to result in a met286-to-thr amino acid substitution (M286T). Three affected members had seizures. Unaided walking was never achieved by 2 and, at age 5, was achieved by a third affected member.
Orthmann-Murphy et al. (2007) stated that this mutation is MET283THR (M283T), when using a different ATG initiation codon. Expression of the mutant M283T protein in HeLa cells showed that the mutant protein partially accumulated in the endoplasmic reticulum, although some was expressed at the cell membrane. Mutant protein that formed membrane puncta did not form functional gap junctions, consistent with a loss of function.
In a nonconsanguineous German family, Uhlenberg et al. (2004) found that a child with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) was compound heterozygous for a C-to-T transition at cDNA position 268 of the GJA12 gene on the paternal allele, predicted to result in a pro90-to-ser amino acid substitution (P90S), and a single-basepair deletion (989delC; 608803.0003) on the maternal allele, leading to a frameshift and a nonsense peptide of 141 amino acids after amino acid 329 (cysteine).
Orthmann-Murphy et al. (2007) stated that this mutation is PRO87SER (P87S), when using a different ATG initiation codon. Expression of the mutant P87S protein in HeLa cells showed that most of the mutant protein accumulated in the endoplasmic reticulum and failed to form functional gap junctions, consistent with a loss of function.
For discussion of the 1-bp deletion in the GJC2 gene (989delC) that was found in compound heterozygous state in a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) by Uhlenberg et al. (2004), see 608803.0002.
In a nonconsanguineous German family, Uhlenberg et al. (2004) studied a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) and found compound heterozygosity for 2 mutations in the GJC2 gene: a C-to-T transition at cDNA position 718 on the paternal allele representing a nonsense mutation (R240X), and a T-to-G transversion at cDNA position 814 on the maternal allele, leading to replacement of tyrosine by aspartic acid (Y272D; 608803.0005).
Using the ATG initiation codon cited by Orthmann-Murphy et al. (2007), this mutation would be ARG237TER (R237X).
For discussion of the tyr272-to-asp (Y272D) mutation in the GJC2 gene that was found in compound heterozygous state in a patient with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804) by Uhlenberg et al. (2004), see 608803.0004.
Orthmann-Murphy et al. (2007) stated that this mutation is TYR269ASP (Y269D), when using a different ATG initiation codon. Expression of the mutant Y269D protein in HeLa cells showed that most of the mutant protein accumulated in the endoplasmic reticulum and failed to form functional gap junctions, consistent with a loss of function.
In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804), Wolf et al. (2007) identified a homozygous 34-bp deletion in the GJA12 gene (del914-947), resulting in a frameshift and a truncated 154-residue peptide. Direct sequencing showed that the deletion was flanked by a 13-bp repeat sequence that may have contributed to formation of the deletion. The 2 sibs showed different clinical phenotypes. The older developed nystagmus at age 4 months, ataxia at 2 years, and spasticity at 6 years. The spasticity progressed, and she was wheelchair-bound by age 16 years. Her younger brother showed nystagmus at age 4 weeks as well as moderately impaired psychomotor development, and was never able to walk independently. He also had a severe sensory neuropathy, which may not have been related to the disorder. Both showed mainly dysmyelination in addition to progressive demyelination on brain MRI.
Salviati et al. (2007) reported the same homozygous 34-bp deletion (del914-947) in another affected Pakistani girl. Both unaffected parents carried the deletion and denied consanguinity. The deletion was not identified in 200 control alleles. Salviati et al. (2007) suggested a loss-of-function effect.
In affected members of 2 presumably unrelated Algerian families with hypomyelinating leukodystrophy (HLD2; 608804), Henneke et al. (2008) identified a homozygous 1-bp insertion (695insG) in the GJC2 gene, resulting in a frameshift and premature termination.
In 3 affected members of an Italian family with spastic paraplegia-44 (SPG44; 613206), Orthmann-Murphy et al. (2009) identified a homozygous 99C-G transversion in the GJC2 gene, resulting in an ile33-to-met (I33M) substitution in a highly conserved region in the first transmembrane domain. The mutation was not found in 210 control alleles. In vitro functional expression assays showed that I33M-mutant protein was able to form gap junctions at apposed cell borders and was present at the cell membrane, but homotypic gap junction channels were not functional. I33M-mutant protein was also able to form heteromeric channels with wildtype Cx43 (GJA1; 121014), but the channels opened only when a large voltage difference that would not be seen under physiologic conditions was applied. Since the mutation resulted in loss of channel function, Orthmann-Murphy et al. (2009) suggested that the comparatively milder phenotype compared to HLD2 (608804) must be due to another functional mechanism.
In multiple affected members of a large 3-generation family with autosomal dominant hereditary lymphedema (LMPHM3; 613480), Ferrell et al. (2010) identified a heterozygous 143C-T transition in the GJC2 gene, resulting in a ser48-to-leu (S48L) substitution in a highly conserved residue in extracellular loop 1. The mutation was not found in 500 control alleles. Affected individuals had early onset, between 0 and 15 years of age, of uncomplicated lymphedema of the lower limbs, and some later developed upper limb involvement. Four individuals had recurrent skin infections. Incomplete penetrance was observed. Ferrell et al. (2010) hypothesized that the mutation may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow.
Ostergaard et al. (2011) identified a heterozygous S48L mutation in affected members of 4 additional families with LMPHM3. One of the families was of Somali origin. The phenotype was similar to that observed by Ferrell et al. (2010).
In multiple affected members of a large 3-generation family with autosomal dominant hereditary lymphedema (LMPHM3; 613480), Ferrell et al. (2010) identified a heterozygous 778C-T transition in the GJC2 gene, resulting in an arg260-to-cys (R260C) substitution in a highly conserved residue in extracellular loop 2. The mutation occurred in the conserved SRPTEK motif, important for connexon docking. The mutation was not found in 500 control alleles. Affected individuals had onset between 10 and 21 years of uncomplicated lymphedema of the lower limbs with upper limb involvement developing later in some. Two patients had cellulitis. Incomplete penetrance was observed. Ferrell et al. (2010) hypothesized that the mutation may result in impaired channel activity, which may cause impaired coordination of pulsatile lymphatic flow.
In a Japanese female with a mild Pelizaeus-Merzbacher-like disorder (HLD2; 608804) who was previously reported by Nezu et al. (1996), Osaka et al. (2010) identified a homozygous -167A-G mutation within the proximal GJC2 promoter that segregated with the disorder. The patient's healthy, second-cousin parents were heterozygous for the mutation, which was not found in 122 normal Japanese chromosomes. The mutation is located within a critical SOX10 binding site (site D) in the syntenic mouse Gjc2 proximal promoter and diminishes the consensus of the SOX binding sequence. Functional studies on the mouse promoter indicated that the -167A-G mutation abolishes SOX10 binding to the GJC2 promoter, resulting in a dramatic attenuation of GJC2 transcription.
Combes et al. (2012) identified the -167A-G mutation in 7 patients with a disorder similar to that in the Japanese patient reported by Osaka et al. (2010). The mutation was homozygous in 5 patients from 4 unrelated families from the same area of south Tunisia and segregated with the disease in a consanguineous family with 2 affected members; it was also found in 2 unrelated patients from the Mediterranean area in compound heterozygosity with another mutation in the GJC2 gene that had been identified by Henneke et al. (2008) in patients with HLD2. The mutation was not found in 212 healthy individuals from the same geographic regions. Functional studies in COS-7 and HEK293 cells demonstrated a higher luciferase expression with the mutated promoter than with the wildtype, suggesting a possible difference in transcription factor recruitment.
Using a new reporter luciferase assay in a human glioblastoma cell line (U138), Gotoh et al. (2014) demonstrated that the -167A-G mutation reduced transcriptional activity compared to wildtype in response to SOX10 (602229). The findings suggested that the mutation disrupts SOX10 binding, resulting in a decrease in the GJC2 expression that is important for the maintenance of myelinating oligodendrocytes.
In a girl, born of consanguineous Sri Lankan parents, with a severe form of hypomyelinating leukodystrophy-2 (HLD2; 608804), Biancheri et al. (2013) identified a homozygous c.787G-A transition in the GJC2 gene, resulting in a glu263-to-lys (E263K) substitution at a highly conserved residue in the extracellular loop-2 domain. (Biancheri et al. (2013) cited the mutation as c.778G-A, resulting in a glu260-to-lys (E260) substitution, based on a different numbering system.) The unaffected parents were heterozygous for the mutation, which was not found in 100 control alleles or in a large control database. Structural analysis predicted that the mutation would disrupt a salt bridge network and hamper correct pore formation and assembly. At birth the patient was noted to have nystagmus, and she subsequently showed severely delayed psychomotor development. Examination at age 7 months showed axial hypotonia, absent head control, increased muscle tone in the lower limbs, and brisk tendon reflexes. Neurophysiologic studies showed abnormal brainstem auditory evoked and visual evoked potentials. Brain MRI showed diffuse hyperintensity on T2-weighted images of the cerebral and cerebellar white matter, including the middle cerebellar peduncles and almost the entire brainstem. The white matter of the cervical spinal cord was also abnormal. At age 5 years, she had not acquired any motor milestones and was severely disabled with spasticity, mental retardation, and poor speech. Funduscopy showed optic atrophy. Biancheri et al. (2013) noted that the phenotype in this patient was consistent with the connatal form of Pelizaeus-Merzbacher disease (PMD).
In 2 unrelated patients with hypomyelinating leukodystrophy-2 (HLD2; 608804), Gotoh et al. (2014) identified a homozygous c.-170A-G transition in the promoter region of the GJC2 gene at a conserved residue within the SOX10 (602229) transcription factor binding site. Parental DNA was not available, but an unaffected sib of 1 of the patients was heterozygous for the mutation, which was not found in the dbSNP (build 139) or 1000 Genomes Project databases. The patients were of Portuguese and Polish descent, respectively. In vitro functional expression in a human glioblastoma cell line (U138) showed that activation by SOX10 was significantly decreased compared to wildtype. Studies in non-glial cells did not yield as significant a difference. The findings suggested that the mutation disrupts SOX10 binding, resulting in a decrease in the GJC2 expression that is important for the maintenance of myelinating oligodendrocytes.
Biancheri, R., Rosano, C., Denegri, L., Lamantea, E., Pinto, F., Lanza, F., Severino, M., Filocamo, M. Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form. Europ. J. Hum. Genet. 21: 34-39, 2013. [PubMed: 22669416] [Full Text: https://doi.org/10.1038/ejhg.2012.93]
Combes, P., Kammoun, N., Monnier, A., Gonthier-Gueret, C., Giraud, G., Bertini, E., Chahnez, T., Fakhfakh, F., Boespflug-Tanguy, O., Vaurs-Barriere, C. Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease. Ann. Neurol. 71: 146-148, 2012. [PubMed: 21246605] [Full Text: https://doi.org/10.1002/ana.22295]
Diekmann, S., Henneke, M., Burckhardt, B. C., Gartner, J. Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction. Europ. J. Hum. Genet. 18: 985-992, 2010. [PubMed: 20442743] [Full Text: https://doi.org/10.1038/ejhg.2010.61]
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Gotoh, L., Inoue, K., Helman, G., Mora, S., Maski, K., Soul, J. S., Bloom, M., Evans, S. H., Goto, Y., Caldovic, L., Hobson, G. M., Vanderver, A. GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease. Molec. Genet. Metab. 111: 393-398, 2014. Note: Erratum: Molec. Genet. Metab. 119: 293 only, 2016. [PubMed: 24374284] [Full Text: https://doi.org/10.1016/j.ymgme.2013.12.001]
Gross, M. B. Personal Communication. Baltimore, Md. 2/27/2014.
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Nezu, A., Kimura, S., Uehara, S., Osaka, H., Kobayashi, T., Haraguchi, M., Inoue, K., Kawanishi, C. Pelizaeus-Merzbacher-like disease: female case report. Brain Dev. 18: 114-118, 1996. [PubMed: 8733901] [Full Text: https://doi.org/10.1016/0387-7604(95)00078-x]
Odermatt, B., Wellershaus, K., Wallraff, A., Seifert, G., Degen, J., Euwens, C., Fuss, B., Bussow, H., Schilling, K., Steinhauser, C., Willecke, K. Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. J. Neurosci. 23: 4549-4559, 2003. [PubMed: 12805295] [Full Text: https://doi.org/10.1523/JNEUROSCI.23-11-04549.2003]
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Orthmann-Murphy, J. L., Salsano, E., Abrams, C. K., Bizzi, A., Uziel, G., Freidin, M. M., Lamantea, E., Zeviani, M., Scherer, S. S., Pareyson, D. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 132: 426-438, 2009. [PubMed: 19056803] [Full Text: https://doi.org/10.1093/brain/awn328]
Osaka, H., Hamanoue, H., Yamamoto, R., Nezu, A., Sasaki, M., Saitsu, H., Kurosawa, K., Shimbo, H., Matsumoto, N., Inoue, K. Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease. Ann. Neurol. 68: 250-254, 2010. [PubMed: 20695017] [Full Text: https://doi.org/10.1002/ana.22022]
Ostergaard, P., Simpson, M. A., Brice, G., Mansour, S., Connell, F. C., Onoufriadis, A., Child, A. H., Hwang, J., Kalidas, K., Mortimer, P. S., Trembath, R., Jeffery, S. Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. J. Med. Genet. 48: 251-255, 2011. [PubMed: 21266381] [Full Text: https://doi.org/10.1136/jmg.2010.085563]
Salviati, L., Trevisson, E., Baldoin, M. C., Toldo, I., Sartori, S., Calderone, M., Tenconi, R., Laverda, A. M. A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease. Neurogenetics 8: 57-60, 2007. [PubMed: 17031678] [Full Text: https://doi.org/10.1007/s10048-006-0065-x]
Uhlenberg, B., Schuelke, M., Ruschendorf, F., Ruf, N., Kaindl, A. M., Henneke, M., Thiele, H., Stoltenburg-Didinger, G., Aksu, F., Topaloglu, H., Nurnberg, P., Hubner, C., Weschke, B., Gartner, J. Mutations in the gene encoding gap junction protein alpha-12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am. J. Hum. Genet. 75: 251-260, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 737 only, 2004. [PubMed: 15192806] [Full Text: https://doi.org/10.1086/422763]
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