Alternative titles; symbols
HGNC Approved Gene Symbol: ARL13B
Cytogenetic location: 3q11.1-q11.2 Genomic coordinates (GRCh38): 3:93,980,155-94,055,678 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q11.1-q11.2 | Joubert syndrome 8 | 612291 | Autosomal recessive | 3 |
The ARL13B gene encodes a member of the ADP-ribosylation factor-like (ARL) family of small GTPases of the RAS superfamily. ARL13B is required for proper cilia formation (summary by Thomas et al., 2015).
In the process of positional cloning of the gene responsible for Bardet-Biedl syndrome type 3 (BBS3; see 209900), which has been mapped to 3p12-q13 by linkage analysis, Fan et al. (2004) identified a gene with a sequence closely related to that of ADP-ribosylation factor-like-2 (ARL2; 601175). They called it ARL2-like protein-1 (ARL2L1). Fan et al. (2004) determined that the C. elegans ARL2L1 ortholog is expressed in ciliated cells. They found no mutations in ARL2L1 in families with BBS3.
In mouse tissues, Cantagrel et al. (2008) found that Arl13b protein was expressed in cilia of all organs examined, including developing cerebellum, distal renal collecting ducts, and the retinal photoreceptor cilia layer connecting the inner and outer segments. About 40% of cilia-like structures in cerebellum showed ARL13B expression at embryonic day 16, compared with 1% of cells by postnatal day 21.
Humbert et al. (2012) identified ARL13B as part of a protein network required for targeting of the phospholipid phosphatase INPP5E (613037) to cilia. Other proteins in the network included the phosphodiesterase PDE6D (602676) and the centriolar protein CEP164 (614848). PDE6D bound the prenylated form of INPP5E, and the GTP-bound form of ARL13B interacted with an adjacent region of INPP5E. Overexpression of ARL13B promoted release of INPP5E from PDE6D. Knockdown of CEP164 or ARL13B reduced or eliminated ciliogenesis in human RPE1 cells, whereas knockdown of PDE6D had little effect on ciliogenesis.
In human embryonic brain tissue, Thomas et al. (2015) found expression of the ALR13B gene in the myelencephalon, the mesencephalon, the metencephalon, the ventricular layer of the diencephalon, the tegmentum of the pons, the cerebellar rhombic lips, and within primary cilia of the ventromedial hypothalamic neurons. ALR13B was also expressed in dorsal root ganglia, the vestibular ganglion, and within the neuronal epithelium surrounding the otic vesicle.
Cantagrel et al. (2008) found that the ARL13B gene comprises 10 coding exons extending over approximately 70 kb of genomic sequence.
Fan et al. (2004) found the ARL13B gene within the BBS3 critical interval on 3p12-q13.
Cantagrel et al. (2008) found the ARL13B gene within chromosome 3p12.3-q12.3.
Within an approximately 110-cM interval on chromosome 3p12.3-q12.3, Cantagrel et al. (2008) identified the ARL13B gene and detected 3 mutations causing Joubert syndrome (JBTS8; 612291). In a consanguineous Pakistani family a missense mutation in the GTP-binding domain was found to segregate with the phenotype (608922.0001). The affected member of a nonconsanguineous United States family was compound heterozygous for 2 additional mutations (608922.0002, 608922.0003).
Humbert et al. (2012) found that 2 missense mutations in ARL13B linked to Joubert syndrome, R79Q (608922.0001) and R200C (608922.0003), disrupted the interaction between ARL13B and INPP5E, resulting in failure to target INPP5E to cilia and failure of ciliogenesis.
In a boy, born of consanguineous Tunisian parents, with JBTS8, Thomas et al. (2015) identified a homozygous missense mutation in the ARL13B gene (Y86C; 608922.0004). The mutation was found by a combination of homozygosity mapping and candidate gene sequencing. Expression of the mutation in arl13b-null zebrafish and mouse embryonic fibroblasts null for Arl13b showed only partial rescue of the null phenotype, consistent with a hypomorphic allele. Thomas et al. (2015) found expression of the ARL13B gene within cilia in ventromedial hypothalamic neurons, and noted that the patient also had obesity. The patient had previously been reported as patient 3 by Romano et al. (2006).
Caspary et al. (2007) described the lethal mouse mutant 'hennin' (hnn), an N-ethyl-N-nitrosourea (ENU)-induced mutation in which the ventrolateral domain of motor neuron progenitors is expanded at the expense of both the most ventral and the most dorsal neural cell types. hnn mutant cilia are short with a specific defect in the structure of the ciliary axoneme, and the hnn neural tube shows an Shh (600725)-independent expansion of the domain of motor neuron progenitors. Limbs and eyes are also affected. Caspary et al. (2007) identified a T-to-G transversion in the splice acceptor site of exon 2 of Arl13b as responsible for the hnn phenotype.
The 'scorpion' (sco) mutation of zebrafish, which results from inactivation of the arl13b gene, displays renal cysts and curved tail, both tied to impaired cilia function (Sun et al., 2004). Cantagrel et al. (2008) found that human wildtype, but not mutated, ARL13B rescued the zebrafish scorpion mutant phenotype.
In a consanguineous Pakistani family with Joubert syndrome (JBTS8; 612291), Cantagrel et al. (2008) identified a G-to-A transition at nucleotide 236 in exon 3 of the ARL13B gene, resulting in an arg-to-gln substitution at codon 79 (R79Q), in homozygosity in affected members. The R79Q mutation occurs within the highly conserved GTP-binding domain and interferes with GTP binding.
In a nonconsanguineous American family with 1 affected female displaying classical Joubert syndrome (JBTS8; 612291), Cantagrel et al. (2008) identified compound heterozygosity for mutations in the ARL13B gene: a G-to-A transition at nucleotide 246 in exon 3, resulting in a stop codon substitution for tryptophan at codon 82 (W82X), and a missense mutation (608922.0003). The W82X mutation was inherited from patient's mother.
In a family with 1 affected female displaying molar tooth sign and other symptoms of Joubert syndrome (JBTS8; 612291), Cantagrel et al. (2008) found that the paternal allele carried a C-to-T transition at nucleotide 598 in exon 5 of the ARL13B gene, resulting in an arg-to-cys substitution at codon 200 (R200C). This mutation occurs in the coiled-coil domain. A premature termination mutation in ARL13B was found on the maternal allele (W82X; 608922.0002).
In a boy, born of consanguineous Tunisian parents, with Joubert syndrome-8 (JBTS8; 612291), Thomas et al. (2015) identified a homozygous c.257A-G transition (c.257A-G, NM_182896.2) in the ARL13B gene, resulting in a tyr86-to-cys (Y86C) substitution at a highly conserved residue. The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing, was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 240 Tunisian control chromosomes. Parental DNA was not available for segregation analysis. Expression of the mutation into arl13b-null zebrafish was only partially able to rescue the phenotype: the curved body was still present, but kidney cysts were not found in 30% of injected mutant zebrafish. Transfection of the mutation into mouse embryonic fibroblasts null for Arl13b also showed only a partial rescue of the null phenotype. The findings were consistent with a hypomorphic allele. In addition to classic features of Joubert syndrome, the patient also had obesity.
Cantagrel, V., Silhavy, J. L., Bielas, S. L., Swistun, D., Marsh, S. E., Bertrand, J. Y., Audollent, S., Attie-Bitach, T., Holden, K. R., Dobyns, W. B., Traver, D., Al-Gazali, L., and 14 others. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am. J. Hum. Genet. 83: 170-179, 2008. [PubMed: 18674751] [Full Text: https://doi.org/10.1016/j.ajhg.2008.06.023]
Caspary, T., Larkins, C. E., Anderson, K. V. The graded response to Sonic hedgehog depends on cilia architecture. Dev. Cell 12: 767-778, 2007. [PubMed: 17488627] [Full Text: https://doi.org/10.1016/j.devcel.2007.03.004]
Fan, Y., Esmail, M. A., Ansley, S. J., Blacque, O. E., Boroevich, K., Ross, A. J., Moore, S. J., Badano, J. L., May-Simera, H., Compton, D. S., Green, J. S., Lewis, R. A., van Haelst, M. M., Parfrey, P. S., Baillie, D. L., Beales, P. L., Katsanis, N., Davidson, W. S., Leroux, M. R. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nature Genet. 36: 989-993, 2004. [PubMed: 15314642] [Full Text: https://doi.org/10.1038/ng1414]
Humbert, M. C., Weihbrecht, K., Searby, C. C., Li, Y., Pope, R. M., Sheffield, V. C., Seo, S. ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proc. Nat. Acad. Sci. 109: 19691-19696, 2012. [PubMed: 23150559] [Full Text: https://doi.org/10.1073/pnas.1210916109]
Romano, S., Boddaert, N., Desguerre, I., Hubert, L., Salomon, R., Seidenwurm, D., Bahi-Buisson, N., Nabbout, R., Sonigo, P., Lyonnet, S., Brunelle, F., Munnich, A., de Lonlay, P. Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study. Neuropediatrics 37: 42-45, 2006. [PubMed: 16541367] [Full Text: https://doi.org/10.1055/s-2006-923838]
Sun, Z., Amsterdam, A., Pazour, G. J., Cole, D. G., Miller, M. S., Hopkins, N. A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney. Development 131: 4085-4093, 2004. [PubMed: 15269167] [Full Text: https://doi.org/10.1242/dev.01240]
Thomas, S., Cantagrel, V., Mariani, L., Serre, V., Lee, J.-E., Elkhartoufi, N., de Lonlay, P., Desguerre, I., Munnich, A., Boddaert, N., Lyonnet, S., Vekemans, M., Lisgo, S. N., Caspary, T., Gleeson, J., Attie-Bitach, T. Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity. Europ. J. Hum. Genet. 23: 621-627, 2015. [PubMed: 25138100] [Full Text: https://doi.org/10.1038/ejhg.2014.156]