GNAL – Dystonia 25

GNAL encodes the Gαolf subunit, a critical mediator of dopamine D1 receptor signaling in the striatum and olfactory bulb. Heterozygous GNAL mutations cause dystonia 25, an adult-onset focal dystonia often involving craniocervical muscles ([PMID:23222958]). Clinical presentation ranges from cervical and laryngeal dystonia to blepharospasm and Meige syndrome, with onset typically in the third to fifth decade.

Initial discovery involved exome sequencing in two families with primary torsion dystonia, identifying a nonsense variant c.878C>G (p.Ser293Ter) segregating in one pedigree and a missense c.409G>A (p.Val137Met) in another; subsequent screening of 39 additional families yielded six more heterozygous variants, confirming GNAL as DYT25 ([PMID:23222958]).

Further case reports include a de novo c.1061T>C (p.Val354Ala) in a sporadic cervical dystonia patient ([PMID:24729450]), two novel heterozygous variants p.Gly213Ser and p.Ala353Thr in German and Japanese cohorts ([PMID:24535567]), and a p.Phe133Leu variant demonstrating loss of function in a Brazilian patient ([PMID:26810727]). None of these variants were detected in unaffected controls or large population databases.

Inheritance is autosomal dominant with evidence of de novo occurrence and segregation in pedigrees; no biallelic or recessive cases have been reported. The mutational spectrum comprises nonsense, frameshift, splice-site, and missense changes consistent with haploinsufficiency as the predominant mechanism.

Functional assessment using bioluminescence resonance energy transfer assays shows that p.Val137Met, p.Ser293Ter, p.Gly213Ser, p.Ala353Thr and p.Phe133Leu markedly impair Gαolf coupling to dopamine D1 receptors, reducing signal amplitude and basal activity ([PMID:23222958])([PMID:24535567])([PMID:26810727]).

A Gnal+/- rat model harboring a 13-bp exon 1 deletion exhibits early-onset motor deficits, impaired locomotion, altered corticostriatal long-term depression, and restored synaptic plasticity upon A2AR blockade, supporting haploinsufficiency and providing an in vivo platform for therapeutic exploration ([PMID:31678405]).

While GNAL variants are infrequent in blepharospasm and Parkinson cohorts, the convergence of multiple independent AD case series, de novo events, segregation data, and concordant functional and animal model evidence establishes a Strong gene–disease association. Key take-home: GNAL haploinsufficiency causes autosomal dominant dystonia 25, warranting inclusion in diagnostic gene panels even for sporadic cases.

References

• Nature Genetics • 2013 • Mutations in GNAL cause primary torsion dystonia. PMID:23222958
• JAMA Neurology • 2014 • Mutations in GNAL: a novel cause of craniocervical dystonia. PMID:24535567
• Movement Disorders • 2014 • De novo mutation in the GNAL gene causing seemingly sporadic dystonia in a Serbian patient. PMID:24729450
• Journal of Neurology • 2016 • Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function. PMID:26810727
• Neurobiology of Disease • 2020 • Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia. PMID:31678405

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