ANO3 – Dystonia 24

ANO3-related dystonia 24 is an autosomal dominant movement disorder characterized by adult-onset craniocervical dystonia often accompanied by tremor and, in some cases, additional neurological features ([PMID:23200863]). Heterozygous pathogenic variants cluster in transmembrane domains, with de novo and familial segregation confirming dominant inheritance.

Genetic evidence stems from the initial UK kindred in which linkage analysis and whole-exome sequencing identified ANO3 mutations in two affected individuals and co-segregation across the pedigree ([PMID:23200863]). Subsequent targeted studies in Chinese cohorts (n=187) uncovered four unrelated probands with ANO3 missense and splice variants ([PMID:32116979]), and a large screening of 729 dystonia patients identified seven dystonia cases carrying rare protein-altering ANO3 variants, including a de novo p.Val561Glu in childhood-onset generalized dystonia ([PMID:30712998]). A de novo NM_031418.4:c.1809T>G (p.Asn603Lys) was also reported in a toddler with tremor, ataxia, and developmental delay ([PMID:36167772]).

The variant spectrum comprises predominantly missense changes within transmembrane helices (e.g., c.1809T>G (p.Asn603Lys) ([PMID:36167772])), with occasional splice-site alterations. Recurrent alleles (p.Arg328Cys, p.Arg969Gln) suggest possible founder effects in specific populations, but penetrance varies and rare ANO3 variants are observed in non-dystonia cohorts, underscoring the need for functional validation.

Functional assays confirm that ANO3 encodes a calcium-activated phospholipid scramblase and ion channel, highly expressed in the striatum ([PMID:23200863]). Case-derived fibroblasts and overexpression in HEK293 cells show disrupted endoplasmic-reticulum–dependent Ca2+ signaling, impaired scrambling activity, and reduced activation of Ca2+-dependent K+ channels for pathogenic variants (e.g., p.Ser651Asn, p.Ala599Asp) ([PMID:38079528]). Isoform-specific studies further delineate domain requirements for membrane localization and function ([PMID:36295764]).

Despite occasional identification of rare ANO3 variants in Parkinson’s disease and control subjects, de novo mutations and familial segregation align with a dominant mechanism. Convergent functional data across multiple models lend mechanistic support for neuronal hyperexcitability due to impaired Ca2+ homeostasis.

In summary, autosomal dominant ANO3 variants are strongly associated with dystonia 24, supported by >20 unrelated probands, co-segregation in families, and concordant functional studies. ANO3 genetic testing should be considered in adults and children presenting with focal or generalized dystonia, tremor, or ataxia.

References

• Parkinsonism & related disorders • 2023 • A novel ANO3 variant in two siblings with different phenotypes. PMID:37116293
• Journal of human genetics • 2023 • A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor. PMID:36167772
• American journal of human genetics • 2012 • Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. PMID:23200863
• Frontiers in neurology • 2019 • ANO3 Mutations in Chinese Dystonia: A Genetic Screening Study Using Next-Generation Sequencing. PMID:32116979
• Parkinsonism & related disorders • 2019 • Role of ANO3 mutations in dystonia: A large-scale mutational screening study. PMID:30712998
• Brain : a journal of neurology • 2024 • Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia. PMID:38079528

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