HPCA – Torsion Dystonia 2

HPCA encodes the neuronal calcium sensor protein hippocalcin, which is highly expressed in the striatum and critical for calcium-dependent signaling in neurons. Biallelic pathogenic variants in HPCA have been causally linked to autosomal recessive torsion dystonia 2 (PMID:25799108) and broadened to include choreo-dystonia and complex neurodevelopmental phenotypes (PMID:36698997). The disorder is designated as torsion dystonia 2 in the MONDO ontology.

1 Assess Clinical Validity

The overall gene–disease relationship is classified as Strong based on 14 probands from 8 unrelated families (PMID:25799108; PMID:36698997), confirmed autosomal recessive segregation in 6 multiplex pedigrees, and concordant functional data demonstrating impaired calcium signaling.

2 Genetic Evidence

Inheritance is autosomal recessive. Segregation of HPCA variants has been demonstrated in 6 additional affected relatives beyond index cases across multiple families. To date, 14 individuals have harbored biallelic HPCA variants, including nonsense and missense changes; for example, a recurrent novel nonsense variant c.49C>T (p.Arg17Ter) was identified in two unrelated Iranian pedigrees (PMID:36698997). Variant spectrum also includes p.Thr71Asn and p.Ala190Thr, affecting calcium-sensor domains.

3 Functional / Experimental Evidence

Cellular assays have shown that hippocalcin mutants (p.Thr71Asn, p.Asn75Lys, p.Ala190Thr) exhibit defective calcium-dependent oligomerization and altered binding to voltage-gated calcium channels (PMID:28398555). The N75K mutant fails to translocate to the plasma membrane during neuronal activity, disrupting slow afterhyperpolarization and increasing neuronal excitability (PMID:31301343). These findings support a loss-of-function mechanism via perturbed calcium signaling.

4 Conflicting Evidence

No studies to date have refuted the association of HPCA variants with torsion dystonia 2; phenotype variability likely reflects allelic heterogeneity and modifier effects.

5 Integration & Conclusion

Genetic evidence of biallelic HPCA variants in 14 probands, segregation in multiple families, and functional assays demonstrating consistent pathobiology establish a strong clinical validity for HPCA in torsion dystonia 2. This knowledge supports diagnostic sequencing of HPCA in patients with early-onset dystonia or choreo-dystonia and may guide the development of therapies targeting calcium-dependent neuronal pathways.

Key Take-home: HPCA should be included in gene panels for autosomal recessive dystonia given robust genetic and functional evidence of pathogenicity.

References

• American Journal of Human Genetics • 2015 • Mutations in HPCA cause autosomal-recessive primary isolated dystonia. PMID:25799108
• Movement Disorders Clinical Practice • 2023 • Childhood-Onset Choreo-Dystonia Due to a Recurrent Novel Homozygous Nonsense HPCA Variant: Case Series and Literature Review. PMID:36698997
• Human Molecular Genetics • 2017 • Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. PMID:28398555
• Neurobiology of Disease • 2019 • Perturbed Ca2+-dependent signaling of DYT2 hippocalcin mutant as mechanism of autosomal recessive dystonia. PMID:31301343

Evidence Based Scoring (AI generated)