HGNC Approved Gene Symbol: RAB23Cytogenetic location: 6p12.1-p11.2 Genomic coordinates (GRCh38): 6:57,186,991-57,222,306 (from NCBI)▼ DescriptionRab proteins...
HGNC Approved Gene Symbol: RAB23
Cytogenetic location: 6p12.1-p11.2 Genomic coordinates (GRCh38): 6:57,186,991-57,222,306 (from NCBI)
Rab proteins are small GTPases of the Ras superfamily involved in the regulation of intracellular membrane trafficking. The RAB23 gene encodes an essential negative regulator of the Sonic hedgehog (SHH; 600725) signaling pathway. For additional background information on Rab proteins, see 179508.
▼ Cloning and Expression
By a map-based approach, Eggenschwiler et al. (2001) cloned the gene mutant in the mouse 'open brain 'phenotype (opb; see later) and found that it encodes Rab23, a member of the Rab family of vesicle transport proteins. The human RAB23 gene encodes a 237-amino acid protein. RAB23 is 30 to 35% identical to other mammalian Rab proteins and includes all the canonical motifs required for guanine nucleotide binding, GTP hydrolysis, membrane association, and the conformational switch between the GTP and GDP-bound state. Rab23 is a relatively divergent Rab protein with an unusually long carboxy-terminal tail. In the mouse at embryonic day 10.5, Rab23 RNA was present at low levels in most tissues, and was present at high levels in the spinal cord, somites, limb buds, and cranial mesenchyme. In the spinal cord, Rab23 was expressed at highest levels in the dorsal half of the neural tube, although it was excluded from the roof plate. In the limb bud, it was expressed in the crescent of mesenchymal cells that are capable of responding to Shh signaling. The expression pattern of Rab23 RNA is similar to that of Gli3 (165240), another negative regulator of the Shh signaling pathway.
▼ Gene Structure
The RAB23 gene contains 8 exons, and the first 2 exons are noncoding (Alessandri et al., 2010).
By database searching, Zhang et al. (2000) mapped the RAB23 gene to chromosome 6p11 based on similarity between the RAB23 sequence (GenBank AF161486) and previously mapped sequences.
▼ Gene Function
Mutations in Shh and opb cause opposing transformations in neural cell fate: Shh mutant embryos lack ventral cell types throughout the spinal cord, whereas opb mutant embryos lack dorsal cell types specifically in the caudal spinal cord. Eggenschwiler et al. (2001) demonstrated that opb acts downstream of Shh. Ventral cell types that are absent in Shh mutants, including the floor plate, are present in Shh-opb double mutants. The organization of ventral cell types in Shh-opb double mutants reveals that Shh-independent mechanisms can pattern the neural tube along its dorsal-ventral axis. Eggenschwiler et al. (2001) concluded that dorsalizing signals activate transcription of Rab23 in order to silence the Shh pathway in dorsal neural cells.
▼ Molecular Genetics
Carpenter syndrome (CRPT1; 201000) is a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. In 15 independent families with Carpenter syndrome, Jenkins et al. (2007) identified 5 different mutations, including 4 truncating (see, e.g., L145X, 606144.0001; 606144.0002) and 1 missense, in the RAB23 gene. In 10 patients, the disease was caused by homozygosity for the same L145X mutation that resides on a common haplotype, indicative of a founder effect in patients of northern European descent. Nonsense mutations of Rab23 in 'open brain' mice were found to cause recessive embryonic lethality with neural tube defects, suggesting a species difference in the requirement for RAB23 during early development. The discovery of RAB23 mutations in patients with Carpenter syndrome implicated HH signaling in cranial suture biogenesis; this was an unexpected finding given that craniosynostosis is not usually associated with mutations of other HH pathway components. The finding also provides a new molecular target for studies of obesity, which is a consistent feature of Carpenter syndrome.
In a consanguineous Comoros Islands pedigree with Carpenter syndrome, Alessandri et al. (2010) identified homozygosity for a 1-bp duplication in the RAB23 gene (606144.0003).
In a female infant, born to consanguineous Turkish parents, with Carpenter syndrome, Haye et al. (2014) identified homozygosity for a missense mutation (V161L; 606144.0004) in the RAB23 gene.
▼ Animal Model
Homozygous 'open brain' (opb) mice die during the second half of gestation, with an open neural tube in the head and spinal cord, abnormal somites, polydactyly, and poorly developed eyes (Gunther et al., 1994). Eggenschwiler et al. (2001) found that the opb mutation arises from the Rab23 gene. The opb1 allele encodes a lys-to-ter mutation at codon 39; the opb2 allele encodes an arg-to-ter mutation at codon 80. These alleles would lack the domains required for guanine nucleotide and Rab effector binding and are therefore null alleles.
▼ ALLELIC VARIANTS ( 4 Selected Examples):
.0001 CARPENTER SYNDROME
In 10 probands with Carpenter syndrome (CRPT1; 201000), including 3 each from the Netherlands and the United Kingdom, 2 from Brazil, and 1 each from the United States and Denmark, Jenkins et al. (2007) found apparent homozygosity for a 434T-A transversion in the RAB23 gene, resulting in a leu145-to-ter (L145X) substitution. A haplotype common to all of these cases was found and shown to contain only 8 genes in addition to RAB23.
.0002 CARPENTER SYNDROME
RAB23, 1-BP INS, 408T
In 2 Brazilian families with Carpenter syndrome (CRPT1; 201000), 1 African/white and the other white, Jenkins et al. (2007) found homozygosity for a 1-bp insertion (408_409insT) in the RAB23 gene, resulting in a glu137-to-ter (E137X) substitution.
.0003 CARPENTER SYNDROME
RAB23, 1-BP DUP, 86A
In 4 boys with Carpenter syndrome (CRPT1; 201000) from a consanguineous Comoros Islands pedigree, Alessandri et al. (2010) identified homozygosity for a 1-bp duplication (86dupA) in the first coding exon of the RAB23 gene, resulting in a premature stop codon (Y29X).
.0004 CARPENTER SYNDROME
In a female infant, born to consanguineous Turkish parents, with Carpenter syndrome (CRPT1; 201000), Haye et al. (2014) identified homozygosity for a c.481G-C transversion (c.481G-C, NM_016277.4) in the RAB23 gene, predicting a val161-to-leu (V161L) substitution at a conserved residue. The mutation occurred 1 bp upstream of the donor splice site of exon 6, resulting in the skipping of exon 6 and a frameshift and premature stop codon (Val161LeufsTer16). The shortened transcript was confirmed by RT-PCR analysis. The parents were heterozygous for the mutation.