ARL13B – Joubert syndrome

ARL13B encodes a small, ciliary GTPase essential for primary cilium structure and Sonic hedgehog (Shh) signaling. Biallelic variants in ARL13B cause Joubert syndrome (JS), an autosomal recessive ciliopathy defined by the “molar tooth sign” on MRI and characterized by cerebellar vermis hypoplasia, ataxia, and variable involvement of the retina, kidneys, liver, and other organs (PMID:18674751).

Genetic evidence for ARL13B–JS includes at least 7 unrelated probands: two families with compound heterozygous or homozygous loss-of-function alleles in two pedigrees (PMID:18674751), a single patient with a homozygous missense c.257A>G (p.Tyr86Cys) presenting with retinal impairment and obesity (PMID:25138100), two consanguineous families with homozygous c.223G>A (p.Gly75Arg) (PMID:29255182), and two patients with novel compound heterozygous missense variants (PMID:38219074). Segregation in consanguineous pedigrees and absence from controls further support pathogenicity.

The variant spectrum comprises at least 16 loss-of-function alleles (nonsense, frameshift, and splice site) and multiple missense changes affecting conserved GTPase and GEF domains (PMID:18674751). No recurrent founder alleles have been reported. The first case report highlighted c.257A>G (p.Tyr86Cys) as a hypomorphic allele associated with obesity, extending the phenotypic spectrum (PMID:25138100).

Functional assays demonstrate that patient variants fail to rescue cilia length and Shh signaling defects in zebrafish scorpion and mouse hennin mutants, confirming loss of ARL13B function (PMID:18674751; PMID:17488627). Biochemical studies show that JS-causing missense variants impair ARL3 GEF activity while retaining GTPase function (PMID:29255182). Retina-specific Arl13b knockout in mice abolishes photoreceptor transition zone assembly and outer segments, reversible by AAV-mediated ARL13B expression (PMID:29089384).

Mechanistically, ARL13B variants act as hypomorphic alleles leading to ciliary dysfunction and disrupted Shh and INPP5E trafficking. In hypothalamic neurons, ARL13B localizes to cilia, linking its loss to obesity via impaired ciliary signaling (PMID:25138100). Genetic interactions with MKS1 and INPP5E place ARL13B upstream in a common ciliopathy pathway (PMID:26490104).

There is no substantial conflicting evidence for ARL13B in JS; all reported variants segregate recessively and concord with model rescue data. Some missense alleles preserve cilia rescue but lose GEF activity, indicating domain-specific functional deficits (PMID:29255182).

In summary, ARL13B fulfills ClinGen criteria for a Strong gene–disease association in autosomal recessive Joubert syndrome, supported by multiple unrelated probands, segregation data, and concordant functional assays. Key take-home: ARL13B testing is clinically useful for JS diagnosis and can inform prognostic considerations including retinal impairment and obesity.

References

• American Journal of Human Genetics • 2008 • Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. PMID:18674751
• European Journal of Human Genetics • 2015 • Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity. PMID:25138100
• European Journal of Human Genetics • 2017 • A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity. PMID:29255182
• Journal of Cellular Physiology • 2024 • Novel compound heterozygous variants in ARL13B lead to Joubert syndrome. PMID:38219074
• Developmental Cell • 2007 • The graded response to Sonic Hedgehog depends on cilia architecture. PMID:17488627
• The Journal of Biological Chemistry • 2017 • The guanine nucleotide exchange factor Arf-like protein 13b is essential for assembly of the mouse photoreceptor transition zone and outer segment. PMID:29089384

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