Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect

Abstract

Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.

Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis

“…The patient identified by us was diagnosed with MD and was on the more severe end of the clinical spectrum as she died at 20 months of age. Three other patients carrying mutations in KARS were also diagnosed with MD and had either neurological dysfunction or cardiomyopathy with early childhood lethality in the former case (Lieber et al., ; McMillan et al., ; Verrigni et al., ); MD was suspected in the three recent cases reported by (Ardissone et al., ). MD was not reported in the remaining patients, for any of which lethality was also not documented.…”

“…Unfortunately, functional data that specifically assesses cytosolic and mitochondrial translation have yet to be provided to test the above hypothesis. In contrast, western immunoblots of muscle homogenates from a patient with compound heterozygous p.(Leu378His) and p.(Pro418Arg) mutations showed a significant decrease in the global level of KARS down to about 50% of control levels suggesting that one or both of these mutations destabilize the proteins (Verrigni et al., ). Indeed, the affected amino acids are located in the catalytic domain and their mutation is associated with predictably significant structural rearrangements that could account for the observed decrease in the steady‐state levels of KARS.…”

“…(), and Verrigni et al. (), OXPHOS enzyme activities were not measured systematically in the other patients and thus it remains unclear if mitochondrial dysfunction underlies the pathology in the remaining patients. Age of onset, when reported, varied from 5–6 weeks to 10 years of age and there was no obvious correlation between age of onset and severity of the disease; a single report documented a fatal outcome for the patient (Lieber et al., ).…”

Mutations inKARScause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism

“…Mutations in AspRS‐encoding DARS [MIM# 603084] and ArgRS‐encoding RARS [MIM# 107820] have been linked to hypomyelination (Taft et al., ), and mutations in GlnRS‐encoding QARS [MIM# 603727] have been shown to cause progressive microcephaly and brain atrophy (Zhang et al., ). Various compound heterozygous recessive mutations in KARS have been previously linked to different clinical phenotypes including the peripheral nerve disorder CMT disease (c.398T > A/c.524_525insTT) (McLaughlin et al., ), nonsyndromic hearing impairment (c.517T > C/c.1129G > A) (Santos‐Cortez et al., ), a syndrome of congenital visual impairment, progressive microcephaly, and cognitive impairment (c.1312C > T/c.1573G > A) (McMillan et al., ), and severe cardiomyopathy associated to mild psychomotor delay and mild myopathy (Verrigni et al., ). In addition, a syndrome of lactic acidosis, developmental delay, hypertrophic cardiomyopathy, seizures, and combined MRC deficiency in a boy and global developmental delay, microcephaly, hypotonia, and sensorineural hearing loss in two sisters have been reported to be associated with mutations in KARS (c.1343T > A/c.953T > C and c.1577C > T/c.1466T > G, respectively) (Kohda et al., ; Murray et al., ).…”

“…The syndrome of lactic acidosis, developmental delay, hypertrophic cardiomyopathy, seizures, and combined MRC deficiency may be also caused by the enzyme defect due to mutations (Kohda et al., ). The pathogenic mechanisms of other mutations in KARS were hypothesized based on structure analysis of LysRS alone and need to be further investigated (McMillan et al., ; Murray et al., ; Santos‐Cortez et al., ; Verrigni et al., ). In this study, we showed that p.R477H and p.P505S mutations occurred at highly conserved positions impacting hLysRS properties in different ways.…”