However, Ahi1 loss in these cells results in: (1) reduced localization of the JBTS-associated protein Arl13b to the ciliary membrane, (2) decreased sonic hedgehog signaling, (3) and an abnormally elongated ciliary axoneme accompanied by an increase in ciliary IFT88 concentrations.
Although AHI1 mutations in humans cause abnormal cerebellar development and impaired axonal decussation in JBTS, these phenotypes are not robust or are absent in various mouse models with Ahi1 mutations.
Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.
Human induced pluripotent stem cells (hiPSCs) from a patient carrying a homozygous missense mutation (c.2168G > A) in AHI1, the first gene to be associated with JS, were produced using a virus-free protocol.
In order to elucidate ciliopathy-associated molecular mechanisms, human induced pluripotent stem cells (hiPSCs) were derived from a patient affected by JS carrying a homozygous missense mutation in the AHI1 gene (p.H896R) that encodes a protein named Jouberin.
Abelson helper integration site 1 (AHI1) is associated with several neuropsychiatric and brain developmental disorders, such as schizophrenia, depression, autism, and Joubert syndrome.
Neuroimaging findings in five JBTS patients with C5orf42 mutations were retrospectively assessed with regard to the infratentorial and supratentorial structures on T1-magnetization prepared rapid gradient echo (MPRAGE), T2-weighted images, and color-coded fractional anisotropy (FA) maps; the findings were compared to those in four JBTS patients with mutations in other genes (including three with AHI1 and one with TMEM67 mutations).
Most AHI1 mutations in JBTS patients result in truncated protein lacking WD40-repeats and the SH3 domain; disease was hitherto attributed to loss of these protein interaction modules.
A deletion of the same genomic interval has also been detected in individuals with Joubert syndrome (JBTS), and in the mouse, Nphp1 interacts genetically with Ahi1, a known JBTS locus.
Our findings suggest that Cend1 is involved in Ahi1-associated hypothalamic neuronal differentiation in early development, giving us fresh insight into the mechanism behind the delayed development in Joubert syndrome.
We show that cells transfected with AHI1-V443D, or a new JBTS-causing mutation, AHI1-R351L, have aberrant localization of AHI1 at the basal bodies of PC and at cell-cell junctions, likely through decreased binding of mutant AHI1 to NPHP1 (another JBTS-causing protein).
AHI1 is expressed in the brain and plays a key role in neurodevelopment, is involved in Joubert syndrome, and has been recently associated with autism.
Mutations in AHI1, which encodes a cilium-localized protein, have been shown to cause a form of Joubert syndrome that is highly penetrant for retinal degeneration.
Here we show that the Abelson helper integration site 1 (Ahi1) gene, whose human ortholog is mutated in Joubert syndrome, regulates cilium formation via its interaction with Rab8a, a small GTPase critical for polarized membrane trafficking.
A significant proportion of patients with JS, in some studies up to 40%, have been diagnosed with autism spectrum disorder (ASD) and several linkage studies in ASD have nominally implicated the region on 6q where AHI1 resides.
Mutations in the Abelson-helper integration site-1 gene (AHI1) cause JBTS in humans, suggesting that AHI1 is required for hindbrain development; however AHI1 may also be required for neuronal function.