Objective: To perform a genetic linkage study with the aim to identify the cause of dyskinesia in a large family with affected members in several generations presenting an autosomal dominant inheritance pattern.

Background: In a multigenerational Danish family stimulus-induced cranial dyskinesia with paroxysmal blepharospasms and pursing of mouth occurs together with musculoskeletal abnormalities and kidney dysfunction. Several causative genes have been identified for paroxysmal dyskinesias. Nonetheless, about 50% of cases remain unexplained. Nail-patella syndrome (NPS) is caused by autosomal dominant mutations in the LMX1B gene, [MIM: 161200], encoding the transcription factor LMX1B, important for cytoskeletal and kidney development, and serotonergic and dopaminergic neuron circuit development in mammalian CNS.

Method: Genome-wide single-nucleotide polymorphism (SNP) microarray analysis was performed for 13 family members and LOD score calculated. Subsequently, six additional family members were analyzed with short tandem polymorphism (STP) and SNP’s and LOD score re-calculated. Whole exome sequencing was followed by Sanger sequencing and Western blotting to confirm presence of novel mutation and gene expression.

Results: Linkage to the 9q32-34.11 locus associated with NPS was found (LOD score Z=4.93). Exome sequencing revealed a novel missense mutation (C>G transition at position chr9: 126693822 (hg38)) in LMX1B. Subsequent analyses confirmed the presence of the mutation in all affected family members with dyskinesia and NPS, as well as in four individuals with musculoskeletal features only (Figure 1). The transition (CAG > GAG) results in a Q to E amino acid change at position 264 in the protein, which is predicted to be damaging. Western blotting confirmed expression of LMX1B in both patients and healthy controls in equal amounts.

Conclusion: We identified a new likely cause of hereditary dyskinesia and its previously unrecognized connection with NPS. We conclude that paroxysmal dyskinesia is a hitherto unrecognized part of the clinical spectrum of NPS. Lack of dyskinesia in four mutation carriers with NPS indicates incomplete penetrance due to an unknown modifier effect. The novel mutation likely results in a toxic gain-of-function effect. We hypothesize that subsequent disruption of dopaminergic function is the underlying cause of the dyskinesia in the family.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/stimulus-induced-paroxysmal-cranial-dyskinesia-and-nail-patella-syndrome-in-a-multigenerational-family-with-a-novel-mutation-in-the-lmx1b-gene/