Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A

Abstract

BackgroundMonogenic defects of synaptic vesicle (SV) homeostasis have been implicated in many neurologic diseases, including autism, epilepsy, and movement disorders. In addition, abnormal vesicle exocytosis has been associated with several endocrine dysfunctions.MethodsWe report an 11 year old girl with learning disabilities, tremors, ataxia, transient hyperglycemia, and muscle fatigability responsive to albuterol sulfate. Failure of neuromuscular transmission was confirmed by single fiber electromyography. Electron microscopy of motor nerve terminals revealed marked reduction in SV density, double‐membrane‐bound sacs containing SVs, abundant endosomes, and degenerative lamellar bodies. The patient underwent whole exome sequencing (WES) and relevant sequence variants were expressed and studied in a mammalian cell line.ResultsChromosomal microarray studies and next generation sequencing (NGS) of mitochondrial DNA were unrevealing; however, NGS of genomic DNA showed two rare sequence variants in the gene encoding rabphilin 3a (RPH3A). The paternally inherited variant c.806 G>A (p.Arg269Gln) involves a substitution of a conserved residue in the linker region, while the maternally inherited variant c.1390 G>T (p.Val464Leu) involves a conserved amino acid substitution in the highly conserved C2A region. Expression studies revealed that p.Arg269Gln strongly impairs the binding of rabphilin 3a to 14‐3‐3, which is a proposed regulator of synaptic transmission and plasticity. In contrast, the binding of rabphilin 3a to 14‐3‐3 is only marginally impaired by p.Val464Leu; thus, the pathogenic role of p.Val464Leu remains unclear.ConclusionIn summary, we report a patient with a multisystem neurologic disorder and altered SV regulation attributed to defects in RPH3A, which grants further studies of this gene in human disorders of synaptic transmission.

Dominant and recessive congenital myasthenic syndromes caused by SYT2 mutations

“…The simplest possibility is that the increase in synaptic vesicle number results from the decrease in evoked release at the terminals, and that the backup of vesicles perturbs trafficking and leads to formation of aberrant vesicular structures. Interestingly, these findings bear some resemblance to those encountered in a carrier of sequence variants in the gene encoding rabphillin 3A, 20 which is another molecule possessing two tandem C2 domains that bind Ca 2+ . Like Syt, rabphillin 3A participates in SV trafficking, docking, fusion, and downstream endocytosis 21,22 …”

Genome‐wide association study of epilepsy in a Japanese population identified an associated region at chromosome 12q24

“…31 Compound heterozygous variants of RPH3A were reported in a patient with learning disabilities, tremors, ataxia, transient hyperglycemia, and muscle fatigability responsive to albuterol sulfate. 32 Moreover, the relevance of rabphilin 3A reduction in Huntington disease in humans and a rodent model has been reported. 31,33 Even with these reports describing the relevance of BRAP and RPH3A variants to neurological diseases, to our knowledge no report describes the relevance of these genes to epilepsy.…”

“…RPH3A is highly expressed in brain, and the encoded protein rabphilin 3A is involved in vesicle docking and recycling and neurotransmitter release 31 . Compound heterozygous variants of RPH3A were reported in a patient with learning disabilities, tremors, ataxia, transient hyperglycemia, and muscle fatigability responsive to albuterol sulfate 32 . Moreover, the relevance of rabphilin 3A reduction in Huntington disease in humans and a rodent model has been reported 31,33 .…”

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…In LEMS-like CMS caused by SYT2 -CMS [ 9 ], VAMP1 -CMS [ 10 ], UNC13A -CMS [ 11 ], RPH3A -CMS [ 12 ], and LAMA5 -CMS [ 13 ], low-frequency RNS causes a decremental CMAP, whereas high-frequency RNS elicits an incremental CMAP [ 14 ]. In another form of LEMS-like CMS of SNAP25 -CMS, low-frequency RNS caused a decremental CMAP, but high-frequency RNS was not examined [ 15 ].…”