PKP2 gene
In 2004, for the first time, Gerull and colleagues reported the link between heterozygous mutations in the PKP2 gene, coding for Plakophilin-2 (PKP2), which is one of the structural components of the cardiac desmosome, part of the Armadillo family of proteins, and known for its role in cell-cell adhesion, and they found that there is a connection between PKP2 expression and the cardiac transcriptional program (Cerrone et al., 2019 ; Cerrone et al., 2017 ). In 2016, a total homozygous PKP2 gene deletion observed in two siblings with severe left ventricular noncompaction cardiomyopathy (LVNC) was identified for the first time, and this homozygous PKP2 gene deletion leads to rapid and lethal cardiac failure in the patient (Ramond et al., 2017 ). According to a study in ARVC patients, frameshift and nonsense mutations account for 35% (79 out of 224) of PKP2 genetic variations identified (Li Mura et al., 2013 ). PKP2 is necessary in maintaining transcription of genes that control intracellular calcium cycling. Lack of PKP2 leads to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias, and may cause life-threatening arrhythmias even in the absence of structural disease (Cerrone et al., 2017 ). In Sonoda et al.’s cohort of 71 clinically diagnosed ARVC patients, one male patient (1.4%), who carries copy number variation (CNV), as the first case of ARVC in Asia, was identified with an extensive PKP2 deletion. The deletion range extended 3’ ofPKP2 , which is novel in ARVC patients (Sonoda et al., 2017 ). The same mutation, c.148_151delACAG, in PKP2 gene in R42 has been reported in clinical cases (Tisma-Dupanovic et al., 2013 ;Philips et al., 2014 ). The patient was a presumed pathogenic mutation, which is heterozygous, in exon 1 of the PKP2 gene (Tisma-Dupanovic et al., 2013 ). Among the 42 arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients in Philips et al., the vast majority (76%) had a pathogenic mutation affecting the PKP2 gene (Philips et al., 2014 ). The same mutation, c.1237C>T, in PKP2 gene in patient R46, who was diagnosed as a ARVD9 patient, has been reported in multiple clinical cases (Campuzano et al., 2014 ; Alcalde et al., 2014 ;Fressart et al., 2010 ). PKP2 associated with the sudden cardiac death (SCD)-disease manifesting earlier onset or more severe presentation of cardiomyopathies (Campuzano et al., 2014 ). Genetic analysis revealed that the truncating PKP2 mutation is the most frequent arrhythmogenic right ventricular cardiomyopathy (ARVC) related genetic variation (Alcalde et al., 2014 ; Fressart et al., 2010 ). The truncated proteins are considered responsible for the pathological phenotype due to their worse functional severity (Alcalde et al., 2014 ).
In our study, we found patient R51 was affected by the heterozygous nonsense mutation c.2490-6T>C in PKP2 gene located on the 12:32945671 chromosome and this mutation leads to a splicing abnormality, thereby causing exon 13 extension. The mutation, c.2490-6T>C, in PKP2 has been reported in Chen et al. The mutation in PKP2 is the most prevalent causation leading to arrhythmogenic cardiomyopathy (ACM) and ventricular arrhythmic events are liable to be developed in the PKP2 mutations carrier (Chen et al., 2019 ). The patient R51 is also a carrier of three heterozygous mutations: (1) a mutation c.1166-51G>A inTRDN gene located on the 6:123702586 chromosome. This variation should be categorized into “uncertain significance” and is related to catecholamin-sensitive pleomorphic ventricular tachycardia type 5 with or without myasthenia, which is autosomal recessive (https://www.omim.org/). (2) a mutation c.80756C>T (p.Pro26919Leu) in TTN gene located on the 2:179430103 chromosome. This variation should be categorized into “uncertain significance” and is related to familial hypertrophic cardiomyopathy type 9 (autosomal dominant), hereditary myopathy with early respiratory failure (autosomal dominant), early onset myopathy with lethal cardiomyopathy (autosomal recessive), dilated cardiomyopathy type 1G (-), delayed tibialis muscle atrophy (autosomal dominant), and limb band muscular dystrophy type 2J (autosomal recessive) (https://www.omim.org/). (3) a mutation c.64508G>T (p.Gly21503Val) in TTN gene located on the 2:179449963 chromosome. This variation should be categorized into “uncertain significance” and is related to familial hypertrophic cardiomyopathy type 9 (autosomal dominant), hereditary myopathy with early respiratory failure (autosomal dominant), early onset myopathy with lethal cardiomyopathy (autosomal recessive), dilated cardiomyopathy type 1G (-), delayed tibialis muscle atrophy (autosomal dominant), and limb band muscular dystrophy type 2J (autosomal recessive) (https://www.omim.org/). But in our case, the patient R51 has no clinical symptom related to above mentioned three gene mutations.