ANK3 – Intellectual Disability

Ankyrin-G, encoded by ANK3, is a key membrane scaffolding protein that clusters ion channels at the axon initial segment and nodes of Ranvier. Rare variants in ANK3 have been implicated across neurodevelopmental disorders, and emerging data support a direct role in Intellectual Disability (PMID:28687526).

Genetic evidence includes a heterozygous de novo nonsense variant c.1990G>T (p.Gly664Ter) identified by trio whole-exome sequencing in a boy with speech impairment, intellectual disability, autistic features, macrocephaly, and macrosomia (PMID:28687526). Prior reports describe three siblings homozygous for a frameshift affecting only the longest AnkG isoform and a patient with a balanced translocation disrupting all transcripts, all presenting with variable intellectual disability, ADHD, and autism (PMID:28687526). A consanguineous Pakistani family harbored a homozygous missense variant c.178T>C (p.Tyr60His) segregating with severe intellectual disability, global developmental delay, seizures, hypotonia, ataxia, speech abnormality, and aggressive behavior (PMID:36777705).

Overall, six probands across three independent families support an autosomal dominant haploinsufficiency mechanism, with evidence for an autosomal recessive hypomorphic effect in the N-terminal region. Segregation data are limited beyond the single index in the recessive pedigree.

Functional studies reinforce ANK3’s critical role in cognitive development. Heterozygous Ank3 knockout mice exhibit increased anxiety-like behavior and neuroanatomical defects in the cingulate and retrosplenial cortices, primary motor cortex, and hippocampal fimbria (PMID:28411148). A knock-in model harboring the W1989R variant that abolishes ANK3/GABARAP interaction shows reduced forebrain GABAergic synapses, pyramidal cell hyperexcitability, and dendritic spine alterations; these deficits are rescue-reversible by restoring Ankyrin-G (PMID:30504823).

No studies have refuted the association between ANK3 loss-of-function and intellectual disability. Integrating genetic, segregation, and concordant functional data defines a model in which ANK3 haploinsufficiency disrupts neuronal connectivity, leading to intellectual disability.

Key take-home: ANK3 loss-of-function variants are a clinically actionable cause of intellectual disability via haploinsufficiency, supported by human and mouse model evidence.

References

• European journal of medical genetics • 2017 • First de novo ANK3 nonsense mutation in a boy with intellectual disability, speech impairment and autistic features. PMID:28687526
• Molecular syndromology • 2023 • Homozygous Missense Variant in the N-Terminal Region of ANK3 Gene Is Associated with Developmental Delay, Seizures, Speech Abnormality, and Aggressive Behavior. PMID:36777705
• Behavioural brain research • 2017 • Behavioural characterization of AnkyrinG deficient mice, a model for ANK3 related disorders. PMID:28411148
• Molecular psychiatry • 2020 • Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP. PMID:30504823

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