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GAP JUNCTION PROTEIN, BETA-4; GJB4

GAP JUNCTION PROTEIN, BETA-4; GJB4

Alternative titles; symbolsCONNEXIN 30.3; CX30.3HGNC Approved Gene Symbol: GJB4Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:34,759,739-34,762...

Alternative titles; symbols

  • CONNEXIN 30.3; CX30.3

HGNC Approved Gene Symbol: GJB4

Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:34,759,739-34,762,326 (from NCBI)

▼ Description
Connexins such as connexin-30.3, encoded by the GJB4 gene, are the protein subunits of gap junction channels, which allow the direct exchange of ions, metabolites, and second messengers up to a molecular mass of 1000 daltons between the cytoplasmic compartments of contacting cells (summary by Plum et al., 2001).

For additional background information on gap junction proteins, see 121011.

▼ Molecular Genetics
Erythrokeratodermia variabilis et progressiva (see EKVP2, 617524) is a genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. In affected members of an Israeli family of Kurdish origin with EKV, in which some patients displayed erythema gyratum repens, originally described by Hacham-Zadeh and Even-Paz (1978), Macari et al. (2000) mapped the disorder to 1p35-p34. Initially they found no mutations in the GJB3 (603324), GJB4, or GJB5 (604493) genes, but further study demonstrated a heterozygous missense mutation in the GJB4 gene (F137L; 605425.0001) that segregated with disease in the family.

In a 4-year-old Dutch boy with the migratory form of EKV, van Geel et al. (2002) identified a heterozygous R32W mutation in the GJB3 gene as well as a homozygous 4-bp deletion (154delGTCT) in the GJB4 gene. Analysis of unaffected family members revealed that both parents and the maternal grandfather were heterozygous for the GJB4 deletion, whereas the mother and maternal grandfather were heterozygous for the GJB3 variant; in addition, the patient's unaffected sister carried the identical GJB3/GJB4 genotype as the patient, thus excluding either DNA variation as causative for the disease. Van Geel et al. (2002) subsequently examined 84 unrelated controls and found 5 heterozygotes for the GJB4 deletion (allele frequency, 0.03) and 3 for the GJB3 variant (0.02), suggesting that both variations represent normal polymorphisms in the Dutch population. Given that the GJB4 knockout mouse does not have an abnormal phenotype, except for a transient placental dysmorphism (Plum et al., 2001), and noting that the proband and his sister represented connexin-30.3 'knockouts,' van Geel et al. (2002) concluded that GJB4 is not an essential gene in humans and that the absence of connexin-30.3 can be compensated by other connexins.

Richard et al. (2003) analyzed the GJB4 gene in 13 unrelated families with EKV who were known to be negative for mutation in GJB3, and identified 6 distinct mutations (605425.0001-605425.0006) in 5 families and a sporadic patient. The F137L substitution (605524.0001), previously identified in an Israeli family of Kurdish origin with EKV and erythema gyratum repens by Macari et al. (2000), was found in 2 families: the identical 409T-C transition was detected in a family with typical EKV, whereas in a 2-year-old boy with EKV and erythema gyratum repens, a 411C-A transversion that also resulted in the F137L substitution was identified (605425.0002). Richard et al. (2003) observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors. Their results confirmed genetic heterogeneity in erythrokeratodermia variabilis, and emphasized that intercellular communication mediated by both CX31 and CX30.3 affects epidermal differentiation significantly.

Plantard et al. (2003) showed that expression of wildtype CX30.3 in HeLa cells resulted only in minor amounts of protein addressed to the plasma membrane. F137L mutant CX30.3 was hardly detectable and disturbed intercellular coupling. In contrast, coexpression of both wildtype CX30.3 and CX31 proteins led to a large increase of stabilized heteromeric gap junctions. Coexpressed wildtype CX30.3 and CX31 coprecipitated, demonstrating a physical interaction. Inhibitor experiments revealed that this interaction began in the endoplasmic reticulum.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2
GJB4, PHE137LEU, 409T-C
In affected members of an Israeli family of Kurdish origin with the migratory form (EKV) of erythrokeratodermia variabilis et progressiva (EKVP2; 617524), in which some patients displayed erythema gyratum repens, originally described by Hacham-Zadeh and Even-Paz (1978), Macari et al. (2000) identified heterozygosity for a 409T-C transition in the GJB4 gene. The mutation results in a phe137-to-leu (F137L) substitution at a highly conserved residue in the third transmembrane domain of the connexin 30.3 molecule, known to be implicated in the wall formation of the gap-junction pore. The mutation was not found in unaffected family members or in 200 alleles from Caucasian controls.

In 3 affected members of a family with the migratory form of erythrokeratodermia variabilis et progressiva, Richard et al. (2003) identified heterozygosity for the 409T-C transition in the GJB4 gene. The mutation was not found in unaffected family members or in 92 unrelated Caucasian controls. The affected boy, his mother, and his maternal grandfather all had localized hyperkeratotic plaques with foci of superficial peeling and red patches mostly confined to the hyperkeratotic areas.

.0002 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2
GJB4, PHE137LEU, 411C-A
In a 2-year-old boy with the migratory form (EKV) of erythrokeratodermia variabilis et progressiva (EKVP2; 617524), Richard et al. (2003) identified heterozygosity for a de novo 411C-A transversion, resulting in the same phe137-to-leu (F137L) substitution in the GJB4 gene previously identified in a family with EKV and erythema gyratum repens by Macari et al. (2000) (see 605425.0001). The mutation was not found in either unaffected parent or in 92 unrelated Caucasian controls. Initially the proband had well-defined, hyperkeratotic plaques symmetrically distributed over the lower extremities and buttocks; the hyperkeratosis progressively worsened, resulting in generalized involvement at the age of 5 years. From 3 months of age, the patient also displayed autonomous erythematous patches with prominent raised circinate borders and rapidly changing configuration, leading to a garland-like appearance (erythema gyratum repens).

.0003 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2
GJB4, THR85PRO
In 16 affected individuals from a 4-generation family segregating autosomal dominant erythrokeratodermia variabilis et progressiva (EKVP2; 617524) over 4 generations, Richard et al. (2003) identified a 253A-C transversion in the GJB4 gene, resulting in a thr85-to-pro substitution predicted to fall within the second transmembrane domain of CX30.3 and hinder regulation of voltage gating or alter the kinetics of channel closure. The mutation was not found in unaffected family members or in 92 unrelated Caucasian controls. Examination of the 16 affected individuals carrying the T85P mutation revealed marked intrafamilial variability of clinical features and striking age-dependent differences: 5 adults between 23 and 70 years of age had no erythematous component at the time of examination but all had a history of 'blotching' and recurring red patches during childhood. In contrast, 5 of 11 children and adolescents showed widely distributed, rapidly changing erythematous patches, and in 4 of them, the erythema had well-defined circinate borders and assumed annular, targetoid, or garland-like shapes (erythema gyratum repens). The extent and localization of hyperkeratosis differed from person to person and during the course of the disease, with 10 of 16 affected individuals having hyperkeratosis limited to a few plaques over large joints, whereas 4 others had larger plaques on the extremities and trunk and mild palmoplantar keratosis, covering more than 25% of their body surface. In addition, 1 mutation-positive individual had neither hyperkeratosis nor erythema when examined at 60 and 62 years of age, although she had an affected child and was reported to have irregular red spots on exposed skin during winter; well-demarcated erythematous patches with an irregular outline were experimentally provoked after 15 minutes at 4 degrees centigrade. Richard et al. (2003) stated that these observations collectively illustrated the intrafamilial clinical heterogeneity and reduced expressivity of the T85P mutation, and indicated that the phenotypic expression of a dominant connexin mutation might critically depend on genetic background and other epigenetic factors, including age, stress, and climate.

.0004 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2
GJB4, GLY12ASP
In 5 individuals with the migratory form (EKV) of erythrokeratodermia variabilis et progressiva (EKVP2; 617524), from 3 different branches of a 7-generation extended Dutch pedigree originally studied by Noordhoek (1950) and later used to map EKV to chromosome 1p by van der Schroeff et al. (1984), Richard et al. (2003) identified heterozygosity for a 35G-A transition in the GJB4 gene, resulting in a gly12-to-asp (G12D) substitution at a highly conserved residue. They speculated that this mutation in the cytoplasmic N-terminal domain might interfere with the flexibility of this domain, connexin selectivity, or gating polarity of gap junction channels. The mutation was not found in unaffected family members or in 92 unrelated Caucasian controls. Clinically, all individuals harboring the G12D mutation showed typical features of EKV without striking phenotypic differences.

.0005 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2
GJB4, ARG22HIS
In a father and daughter with the migratory form (EKV) of erythrokeratodermia variabilis et progressiva (EKVP2; 617524), Richard et al. (2003) identified heterozygosity for a G-to-A transition in the GJB4 gene, resulting in an arg22-to-his (R22H) substitution in the first transmembrane domain of CX30.3. This mutation was predicted to hinder regulation of voltage gating or alter the kinetics of channel closure. The mutation was not found in unaffected family members or in 92 unrelated Caucasian controls. The clinical features included symmetric hyperkeratotic plaques with faint underlying erythema on the extremities as well as transient red patches; the father reported marked age-related regression of both morphologic components.

.0006 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2
GJB4, PHE189TYR
In affected members of a large 3-generation family with the migratory form (EKV) of erythrokeratodermia variabilis et progressiva (EKVP2; 617524), Richard et al. (2003) identified heterozygosity for a 566T-A transversion in the GJB4 gene, resulting in a phe198-to-tyr (F189Y) substitution at a conserved residue within the fourth transmembrane domain of CX30.3 that was predicted to hinder regulation of voltage gating or alter the kinetics of channel closure. The mutation was not found in unaffected family members or in 92 unrelated Caucasian controls. In contrast to other families with mutations in GJB4, the prevailing features in this family were severe hyperkeratosis with accentuated skin markings, ridging in large skin folds, and noticeable hypertrichosis lanuginosa (see 145700) with sparing of palms, soles, and scalp.

Tags: 1p34.3