Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

Abstract

Joubert syndrome (JS) is a genetically heterogeneous autosomal recessive ciliopathy with 22 genes implicated to date, including a small, ciliary GTPase, ARL13B. ARL13B is required for cilia formation in vertebrates. JS patients display multiple symptoms characterized by ataxia due to the cerebellar vermis hypoplasia, and that can also include ocular abnormalities, renal cysts, liver fibrosis or polydactyly. These symptoms are shared with other ciliopathies, some of which display additional phenotypes, such as obesity. Here we identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient who displayed retinal defects and obesity. We demonstrate the variant disrupts ARL13B function, as its expression did not rescue the mutant phenotype either in Arl13b scorpion zebrafish or in Arl13b hennin mouse embryonic fibroblasts, while the wild-type ARL13B did. Finally, we show that ARL13B is localized within the primary cilia of neonatal mouse hypothalamic neurons consistent with the known link between hypothalamic ciliary function and obesity. Thus our data identify a novel ARL13B variant that causes JS and retinopathy and suggest an extension of the phenotypic spectrum of ARL13B mutations to obesity.

Arl13b regulates Shh signaling from both inside and outside the cilium

“…Some point mutations in ARL13B are compatible with life and are linked to the human ciliopathy JS (Cantagrel et al ., 2008). Previous studies identified JS patients with homozygous R79Q and Y86C mutations in ARL13B , as well as with an R200C mutation in combination with a truncating mutation (Cantagrel et al ., 2008; Thomas et al ., 2015). …”

Hypomorphism of Fto and Rpgrip1l causes obesity in mice

“…As with FTO-deficient individuals, these patients display skeletal and CNS developmental defects that may mask a role of RPGRIP1L in energy homeostasis. A recent report described an obese patient with Joubert syndrome with mutations at ARL13B and similar brain abnormalities as those of individuals with RPGRIP1L-inactivating mutations but with no apparent skeletal anomalies (47), suggesting that CNS abnormalities caused by RPGRIP1L haploinsufficiency may cause obesity in humans.…”

The cilium: a cellular antenna with an influence on obesity risk

“…When a mutated ciliary gene leads to Joubert syndrome, obesity is commonly not part of the symptoms. However, recently, a patient with Joubert syndrome and obesity has been reported with a homozygous missense mutation in the ARL13B gene, which affects ciliogenesis (21) . Besides clinical presentation, animal studies may also reveal new interesting genes in this cilia-obesity context.…”

“…Differences have also been observed with regard to the severity and age-of-onset of obesity. Comparing BBS2 patients and BBS4 patients, Carmi et al (129) found that for BBS2 obesity was relatively mild, (99,120) ARL13B* Required for ciliogenesis (21,121) B9D1 Transition zone; basal body BBS19/IFT27/RABL4* Component of the IFT-B particle, plays a role in BBS3 activation during retrograde transport (93) CC2D2A Transition zone; basal body (4,102) CEP19* Transition fibre (98) …”

“…What may happen is that, when the BTC reaches the top of the cilium, BBS3/ARL6-bound GTP is hydrolysed, perhaps by the action of the Rab-like GTPase IFT27, and as a consequence BBSomes are released from the membrane. Next, the release of IFT27 allows the activation of BBS3/ARL6 by GTP binding and attachment of (20) Joubert Syndrome 8 612291 ARL13B Yes (21) Meckel Syndrome 9 614209 B9D1 No (22) Bardet-Biedl Syndrome 1 209900 BBS1 Yes (15,(23)(24)(25) Bardet-Biedl Syndrome 2 615981 BBS2 Yes (23,25,26) Bardet-Biedl Syndrome 3 600151 BBS3/ARL6 Yes (27) Bardet-Biedl Syndrome 4 600374 BBS4 Yes (23,25,28) Bardet-Biedl Syndrome 5 615983 BBS5 Yes (23,29) Bardet-Biedl Syndrome 6 605231 BBS6/MKKS Yes (25,30) Bardet-Biedl Syndrome 7 615984 BBS7 Yes (23) Bardet-Biedl Syndrome 8 608132 BBS8/TTC8 Yes (23)(24)(25) Bardet-Biedl Syndrome 9 615986 BBS9/PTHB1 Yes (31) Bardet-Biedl Syndrome 10 615987 BBS10 Yes (15,23,25,32) Bardet-Biedl Syndrome 11 615988 BBS11/TRIM32 No (33) Limb-girdle muscular dystrophy 2H 254110 Id. No (34) Bardet-Biedl Syndrome 12 615989 BBS12 Yes (23) Bardet-Biedl Syndrome 13 615990 BBS13/MKS1 Yes (15,35) Meckel Syndrome 1 249000 Id.…”