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Lymphedema Gene GJC2

As the pace of Lymphedema research increases, we are pleased to include our newest Lymphedema gene information page. This newly discovered gene is called the GJC2.

This brings the total now to some six specific genes involved in causing one form of hereditary Lymphedema or another.

While the GJC2 has been studied before, this is the first time it has been found to be connected to dominantly inherited Lymphedema.

Pat

GJC2 Missense Mutations Cause Human Lymphedema

Am J Hum Genet. 2010 May 26

Ferrell RE, Baty CJ, Kimak MA, Karlsson JM, Lawrence EC, Franke-Snyder M, Meriney SD, Feingold E, Finegold DN. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. Abstract

Lymphedema is the clinical manifestation of defects in lymphatic structure or function. Mutations identified in genes regulating lymphatic development result in inherited lymphedema. No mutations have yet been identified in genes mediating lymphatic function that result in inherited lymphedema. Survey microarray studies comparing lymphatic and blood endothelial cells identified expression of several connexins in lymphatic endothelial cells. Additionally, gap junctions are implicated in maintaining lymphatic flow. By sequencing GJA1, GJA4, and GJC2 in a group of families with dominantly inherited lymphedema, we identified six probands with unique missense mutations in GJC2 (encoding connexin [Cx] 47). Two larger families cosegregate lymphedema and GJC2 mutation (LOD score = 6.5). We hypothesize that missense mutations in GJC2 alter gap junction function and disrupt lymphatic flow. Until now, GJC2 mutations were only thought to cause dysmyelination, with primary expression of Cx47 limited to the central nervous system. The identification of GJC2 mutations as a cause of primary lymphedema raises the possibility of novel gap-junction-modifying agents as potential therapy for some forms of lymphedema.

PubMed

Researchers discover gene mutation linked to lymphatic dysfunction

Preface from PDF article Lymphedema is the clinical manifestation of defects in lymphatic structure or function. Mutations identified in genes regulating lymphatic development result in inherited lymphedema. No mutations have yet been identified in genes mediating lymphatic function that result in inherited lymphedema. Survey microarray studies comparing lymphatic and blood endothelial cells identified expression of several connexins in lymphatic endothelial cells. Additionally, gap junctions are implicated in maintaining lymphatic flow.

By sequencing GJA1, GJA4, and GJC2 in a group of families with dominantly inherited lymphedema, we identified six probands with unique missense mutations in GJC2 (encoding connexin [Cx] 47). Two larger families cosegregate lymphedema and GJC2 mutation (LOD score ¼ 6.5). We hypothesize that missense mutations in GJC2 alter gap junction function and disrupt lymphatic flow. Until now, GJC2 mutations were only thought to cause dysmyelination, with primary expression of Cx47 limited to the central nervous system. The identification of GJC2 mutations as a cause of primary lymphedema raises the possibility of novel gap-junction-modifying agents as potential therapy for some forms of lymphedema.*

A genetic mutation for inherited lymphedema associated with lymphatic function has been discovered that could help create new treatments for the condition, say researchers at the University of Pittsburgh Graduate School of Public Health.

Their findings are reported in the June issue of the American Journal of Human Genetics.

Lymphedema, the swelling of body tissues caused by an accumulation of fluid in a blocked or damaged lymphatic system, affects more than 120 million people worldwide. The most common treatments are a combination of massage, compression garments or bandaging.

“Lymphedema was first described hundreds of years ago, and yet it remains a very poorly understood disease,” said David N. Finegold, M.D., co-principal investigator of the study and professor of human genetics, University of Pittsburgh Graduate School of Public Health. “Unfortunately, there is no drug available to cure or even treat it. Most people with inherited lymphedema suffer their entire lives with treatments that address symptom relief only.”

The study is based on the University of Pittsburgh Lymphedema Family Study, which began collecting data from affected families in 1995 to learn more about the risk factors and causes of inherited, or primary, lymphedema.

Previous research has helped identify six genes linked to the development of lymphedema, but until now researchers had no insight into the genetic factors responsible for lymphatic vascular abnormalities.

In their study, Dr. Finegold and colleagues sequenced three genes expressed in families with primary lymphedema. Mutations in one of these genes, GJC2, was found in primary lymphedema families and are likely to impair the ability of cells to push fluid throughout the lymphatic system by interrupting their signaling.

Without proper signaling, cell contraction necessary for the movement of fluid did not occur, leading to its accumulation in soft body tissues.

“These results are significant because they give us insight into the cell mechanics that may underlie this condition,” said Dr. Finegold. “With further research, we may be able to target this gene with drugs and improve its function.”

More information PDF article:

The American Journal of Human Genetics

Gene Mutation Linked to Lymphatic Dysfunction

Researchers at the University of Pittsburgh Graduate School of Public Health discovered a genetic mutation for inherited lymphedema associated with lymphatic function. This could help create new treatments for the condition, say the researchers. Their findings are reported in the June issue of the American Journal of Human Genetics.

Currently, the most common treatments for lymphedema are a combination of massage, compression garments, or bandaging.

“Lymphedema was first described hundreds of years ago, and yet it remains a very poorly understood disease,” said David N. Finegold, MD, co-principal investigator of the study and professor of human genetics at the school. “Unfortunately, there is no drug available to cure or even treat it. Most people with inherited lymphedema suffer their entire lives with treatments that address symptom relief only.”

The study is based on the University of Pittsburgh Lymphedema Family Study, which began collecting data from affected families in 1995 to learn more about the risk factors and causes of inherited, or primary, lymphedema.

Previous research identified six genes linked to the development of lymphedema, but researchers had no insight into the genetic factors responsible for lymphatic vascular abnormalities until now.

Finegold and colleagues sequenced three genes expressed in families with primary lymphedema. Mutations in one of these genes, GJC2, were found in primary lymphedema families and are likely to impair the ability of cells to push fluid throughout the lymphatic system by interrupting their signaling. Without proper signaling, cell contraction necessary for the movement of fluid does not occur, leading to its accumulation in soft body tissues.

Previous research identified six genes linked to the development of lymphedema, but researchers had no insight into the genetic factors responsible for lymphatic vascular abnormalities until now.

Finegold and colleagues sequenced three genes expressed in families with primary lymphedema. Mutations in one of these genes, GJC2, were found in primary lymphedema families and are likely to impair the ability of cells to push fluid throughout the lymphatic system by interrupting their signaling. Without proper signaling, cell contraction necessary for the movement of fluid does not occur, leading to its accumulation in soft body tissues.

“These results are significant because they give us insight into the cell mechanics that may underlie this condition,” said Finegold in an announcement. “With further research, we may be able to target this gene with drugs and improve its function.”

Photo: David N. Finegold, MD, courtesty of University of Pittsburgh.

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GJC2 Gene

Aliases & Description

gap junction protein, gamma 2, 47kDa1 2

   	gap junction protein, alpha 12, 47kDa1

GJA122 3 5

   	connexin 472

CX46.61 2

   	MGC1051192

SPG441 2

   	connexin46.62

Cx472 3

   	Connexin-46.63

CX471 5

   	Cx46.63

HLD22 5

   	Connexin-473

PMLDAR2 5

   	Gap junction alpha-12 protein3

External Ids: HGNC: 174941 Entrez Gene: 571652 Ensembl: ENSG000001988357 UniProtKB: Q5T4423

EntrezGene summary for GJC2:

This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. (provided by RefSeq)

UniProtKB/Swiss-Prot: CXG2_HUMAN, Q5T442 Function: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a role in myelination in central and peripheral nervous systems

Summary for GJC2: Gap channels (also known as gap junctions) are specalized cell-cell contacts between almost all eukaryotic cells that provide direct intracellular communication. Generally, gap channels allow the passive diffusion of molecules up to 1 kDa which includes nutrients, small metabolites (e.g. glucose), ions (K+, Ca2+) and second messengers (IP3, cAMP and cGMP). Gap channels allow electrical and biochemical coupling between cells and in excitable tissues, such as neurons and the heart, enables the generation of synchronized and rapid responses. Structurally, gap channels are composed of two hemichannels called 'connexons', which themselves are formed from six connexin molecules. Homo- and heteromeric combinations are seen, which exhibit distinct permeability, selectivity and functional properties. Pannexins are related to connexins and can also form gap junctions. However, their expression is limited to the brain. Furthermore, in nonchordate animals a family of proteins called innexins form these channels. Gap channels are regulated through post-translational modifications of the C'-terminal cytoplasmic tail and phosphorylation modulates assembly and their physiological properties. They are continuously synthesized and degraded, allowing tissues to rapidly adapt to changing environmental conditions. Connexins play a key role in many physiological processes including cardiac and smooth muscle contraction, regulation of neuronal excitability, epithelial electrolyte transport and keratinocyte differentiation. Mutations in connexin genes are associated with human diseases including sensorineural deafness, a variety of skin disorders, peripheral neuropathy and cardiovascular disease.

GeneCards

GAP JUNCTION PROTEIN, GAMMA-2; GJC2

MIM *0608803

Alternative titles; symbols •GAP JUNCTION PROTEIN, ALPHA 12; GJA12 •GAP JUNCTION PROTEIN, 47-KD •CONNEXIN 47; CX47 CONNEXIN 46.6; CX46.6

Gene map locus: 1q41-q42

Text

For background information on connexins, see CX26 (GJB2; 121011).

Cloning

The complete coding sequence of the GJA12 gene has been deposited in GenBank (AF014643). The GJA12 sequence encodes a 436-amino acid protein (GenBank AAB94511).

Gene Function

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).

Gene Structure

The GJA12 gene consists of a single exon (Uhlenberg et al., 2004).

Mapping

The GJA12 gene maps to chromosome 1q41-q42 (Uhlenberg et al., 2004).

Molecular Genetics

Hypomyelinating Leukodystrophy 2

In a consanguineous Turkish family and 2 nonconsanguineous German families with autosomal recessive hypomyelinating leukodystrophy (HLD2; 608804), 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 displayed toxic gain of function in oligodendrocytes.

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.

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.

Animal Model

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.

Allelic Variants

(Selected Examples) Notes

See allelic variants in tabular display

.0001 LEUKODYSTROPHY, HYPOMYELINATING, 2 [GJC2, MET286THR ] dbSNP:rs74315311 In a consanguineous Turkish family, Uhlenberg et al. (2004) found that members with autosomal recessive hypomyelinating leukodystrophy (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.

.0002 LEUKODYSTROPHY, HYPOMYELINATING, 2 [GJC2, PRO90SER ] dbSNP:rs74315312 In a nonconsanguineous German family, Uhlenberg et al. (2004) found that a child with autosomal recessive hypomyelinating leukodystrophy (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, on the maternal allele, leading to a frameshift and a nonsense peptide of 141 amino acids after amino acid 329 (cysteine).

.0003 LEUKODYSTROPHY, HYPOMYELINATING, 2 [GJC2, 1-BP DEL, 989C] See 608803.0002 and Uhlenberg et al. (2004).

.0004 LEUKODYSTROPHY, HYPOMYELINATING, 2 [GJC2, ARG240TER ] dbSNP:rs74315313 In a nonconsanguineous German family, Uhlenberg et al. (2004) studied a patient with autosomal recessive hypomyelinating leukodystrophy (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).

.0005 LEUKODYSTROPHY, HYPOMYELINATING, 2 [GJC2, TYR272ASP ] dbSNP:rs74315314 See 608803.0004 and Uhlenberg et al. (2004).

.0006 LEUKODYSTROPHY, HYPOMYELINATING, 2 [GJC2, 34-BP DEL, NT914] In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive hypomyelinating leukodystrophy (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, 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.

.0007 LEUKODYSTROPHY, HYPOMYELINATING, 2 [GJC2, 1-BP INS, 695G ] In affected members of 2 presumably unrelated Algerian families with hypomyelinating leukodystrophy (608804), Henneke et al. (2008) identified a homozygous 1-bp insertion (695insG) in the GJC2 gene, resulting in a frameshift and premature truncation.

.0008 SPASTIC PARAPLEGIA 44 [GJC2, ILE33MET ] 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.

References 1. Henneke, M., Combes, P., Diekmann, S., Bertini, E., Brockmann, K., Burlina, A. P., Kaiser, J., Ohlenbusch, A., Plecko, B., Rodriguez, D., Boespflug-Tanguy, O., Gartner, J. GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease. Neurology 70: 748-754, 2008. [PubMed: 18094336] 2. Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S., Paul, D. L. Connexins are critical for normal myelination in the CNS. J. Neurosci. 23: 5963-5973, 2003. [PubMed: 12843301] 3. 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] 4. 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] 5. 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. Neurogenetics8: 57-60, 2007. [PubMed: 17031678] 6.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] 7. Wolf, N. I., Cundall, M., Rutland, P., Rosser, E., Surtees, R., Benton, S., Chong, W. K., Malcolm, S., Ebinger, F., Bitner-Glindzicz, M., Woodward, K. J. Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination. Neurogenetics 8: 39-44, 2007. [PubMed: 16969684]

Contributors

Cassandra L. Kniffin - updated : 1/6/2010 Cassandra L. Kniffin - updated : 1/6/2009 Cassandra L. Kniffin - updated : 2/28/2007 Anne M. Stumpf - updated : 7/16/2004

Creation Date Victor A. McKusick : 7/15/2004

Edit wwang: 1/21/2010

Online Mendelian Inheritance in Man

Lymphedema Family Study - Genetics

This is perhaps one of the most important centers for us as lymphedema patients. The pace of genetic research is exploding and it will be through this type of research that we will come to know and understand:

1.) What causes lymphedema - the genetics involved.

2.) The path to a genetic cure

3,) The ability to provide treatment.

How many times have we said, “we wished someone could find out what causes lymphedema?” Countless, countless times.

The serious problem we face now is that due to the economy funding programs for this research has almost dried up and the program in very much in danger of being shutdown early next year.

Friends, we absolutely must save this program. Should it be closed, we would loose just about our only hope of a cure. We would also loose some of the most committed doctors, and support staff.

Please visit the site and go through their information. Support them as much as it is possible.

Pat O'Connor

University of Pittsburg

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lymphedema_gene_gjc2.txt · Last modified: 2012/10/16 14:40 (external edit)