PNKD – Tourette Syndrome

In a three-generation family with Tourette Syndrome, a rare heterozygous nonsense mutation in PNKD co-segregated with TD in four affected relatives, supporting autosomal dominant inheritance with functional concordance (PMID:28894297). Whole exome sequencing of six family members (three affected, three unaffected) revealed transcript and protein reduction of the PNKD long isoform in patient-derived neurons due to nonsense-mediated decay. This represents a single multiplex pedigree; no additional unrelated probands have been reported.

Functional studies using induced pluripotent stem cell–derived neurons from affected individuals demonstrated that the PNKD long isoform oligomerizes and interacts with synaptic active zone protein RIMS1α, implicating disrupted synaptic regulation as a pathogenic mechanism. These cellular assays provide moderate experimental support but await replication in independent cohorts.

Key Take-home: While preliminary, PNKD haploinsufficiency emerges as a candidate mechanism in familial Tourette Syndrome, and targeted screening in multiplex TD families may aid diagnosis and inform mechanistic studies.

References

• Molecular psychiatry • 2018 • The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family. PMID:28894297

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