We report a missense change in the PRRT2
gene associated with familial PKD with mild phenotype and reduced penetrance. Although the pathogenicity of this alteration cannot be proven, it changes a highly conserved amino acid residue (),9
was predicted by PolyPhen-2 to be deleterious, and was not identified across 1,000 individuals in our in-house exome database, in 1,092 individuals sequenced in the 1000 Genomes database,10
or among variants identified by Chen et al.2
in 500 Han Chinese control subjects. Recently, this missense change has also been identified by Liu et al.5
in a patient with sporadic PKD, consistent with its pathogenicity.
Previous studies reported PKD attack frequency of greater than 20 per day in 31% of patients and at least once per day in 72%.8
Comparatively, the phenotype in this family is mild with 2 siblings with infrequent symptoms requiring carbamazepine only rarely. In addition, the mother is a nonsymptomatic carrier. Although the mutation identified in this single family is insufficient to establish a clear genotype-phenotype correlation, it is possible that the missense mutation leads to partial loss of function and a milder phenotype. Nevertheless, additional modifiers are probably at play, because PRRT2
kindreds can display phenotypic variability that may include infantile convulsions.6
Other neurologic symptoms have also been reported in patients and kindreds with PKD although no definitive association has been established.8
These symptoms include dystonia and tics, which were also noted in our patients.
The PRRT2 protein contains 2 extracellular domains, 2 transmembrane domains, and 1 cytoplasmic domain.2
The majority of reported mutations to date lead to premature transcription termination and truncated protein products. In vitro, truncated products have been found to mis-localize from membrane to cytoplasm2
or, alternatively, to be poorly expressed, resulting in haploinsufficiency.7
Reports of patients with possible PKD with deletions encompassing the PRRT2
support the idea that haploinsufficiency can result in the PKD phenotype.
The c.913G>A mutation is a missense substitution, located in exon 3, that codes for a change in the cytoplasmic region of the protein. Although we lack functional data, it is likely that this mutation leads to partial loss of function of the affected allele through an as yet undefined mechanism. It has been proposed that PKD is an ionic channelopathy and that PRRT2 may complex with or regulate key properties of ion channels2
or that that PKD may result from dysfunction of synaptic regulation due to interaction with SNAP25.7
However, the precise role PRRT2
mutations play in PKD remains unknown.
Further study of this and other families will be necessary to establish genotype-phenotype correlations, to confirm the pathogenicity and mechanism of action of the c.913G>A (p.Gly305Arg) change, to identify the spectrum of genetic variations in PRRT2 associated with PKD, and to determine the possible association of PRRT2 mutations with other movement disorders including dystonia and tics.