Allelic and phenotypic heterogeneity in Junctophillin-3 related neurodevelopmental and movement disorders

Thomas Bourinaris,Alkyoni Athanasiou,Sarah Wiethoff,Vincenzo Salpietro,Stephanie Efthymiou,Henry Houlden

doi:10.1038/s41431-021-00866-1

Abstract

Junctophilin-3 belongs to a triprotein junctional complex implicated in the regulation of neuronal excitability and involved in the formation of junctional membrane structures between voltage-gated ion channels and endoplasmic (ryanodine) reticular receptors. A monoallelic trinucleotide repeat expansion located within the junctophilin-3 gene (JPH3) has been implicated in a rare autosomal dominant (AD) late-onset (and progressive) disorder clinically resembling Huntington disease (HD), and known as HD-like 2 (HDL2; MIM# 606438). Although the exact molecular mechanisms underlying HDL2 has not yet been fully elucidated, toxic gain-of-function of the aberrant transcript (containing the trinucleotide repeat) and loss of expression of (full-length) junctophilin-3 have both been implicated in HDL2 pathophysiology. In this study, we identified by whole exome sequencing (WES) a JPH3 homozygous truncating variant [NM_020655.4: c.17405dup; p.(Val581Argfs*137)]. in a female individual affected with genetically undetermined neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. Our study expands the JPH3-associated mutational spectrum and clinical phenotypes, implicating the loss of Junctophilin-3 in heterogeneous neurodevelopmental phenotypes and early-onset paroxysmal movement disorders.

Highlights

Huntington’s disease (HD)-like 2 (HDL2) is a progressive autosomal dominant (AD) neurodegenerative disorder reported to be almost indistinguishable clinically from HD [1]
The variant was absent from the GnomAD database where only three LoF variants are reported in the junctophilin-3 gene (JPH3) gene [(p. (Trp81Ter), p.(Lys310Ter), p.(Ile741Thrfs*8)], all of them in the heterozygous state
CUG repeat expansion have been shown to cause cellular toxicity, suggesting that the RNA transcripts play an important role in the HD-like 2 (HDL2) pathogenesis via a toxic RNA gain-of-function effect [13]; loss of fulllength JPH3 protein expression has been potentially implicated in the disease pathogenesis [1]

Summary

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Huntington’s disease (HD)-like 2 (HDL2) is a progressive autosomal dominant (AD) neurodegenerative disorder reported to be almost indistinguishable clinically from HD [1]. A diagnosis of cerebral palsy was made in the first months of life and she was found to have delayed developmental milestones, including motor difficulties and abnormal social communication and language Later on, she was diagnosed with learning difficulties and speech impairment. Since the second year of her life, she showed a movement disorder phenotype consisting of frequent episodes of generalized dystonic posturing affecting the trunk, neck and upper limbs bilaterally. During these episodes the girl experienced speech difficulties, facial flushing and, occasionally, muscle weakness resulting in frequent falls without loss of consciousness (Video 1). There is a bilateral fine rest, postural and intentional tremor, while cerebellar tests show significant dysmetria upon finger-

Materials and methods

Results

Discussion

Compliance with ethical standards