Cellular mechanisms underlying the increased disease severity seen for patients with long QT syndrome caused by compound mutations in KCNQ1

Abstract

The KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene encodes the Kv7.1 potassium channel which forms a complex with KCNE1 (potassium voltage-gated channel Isk-related family member 1) in the human heart to produce the repolarizing IKs (slow delayed rectifier potassium current). Mutations in KCNQ1 can perturb IKs function and cause LQT1 (long QT syndrome type 1). In LQT1, compound mutations are relatively common and are associated with increased disease severity. LQT1 compound mutations have been shown to increase channel dysfunction, but whether other disease mechanisms, such as defective channel trafficking, contribute to the increase in arrhythmic risk has not been determined. Using an imaging-based assay we investigated the effects of four compound heterozygous mutations (V310I/R594Q, A341V/P127T, T391I/Q530X and A525T/R518X), one homozygous mutation (W248F) and one novel compound heterozygous mutation (A178T/K422fs39X) (where fs denotes frameshift) on channel trafficking. By analysing the effects in the equivalent of a homozygous, heterozygous and compound heterozygous condition, we identify three different types of behaviour. A341V/P127T and W248F/W248F had no effect, whereas V310I/R594Q had a moderate, but not compound, effect on channel trafficking. In contrast, T391I/Q530X, A525T/R518X and A178T/K422fs39X severely disrupted channel trafficking when expressed in compound form. In conclusion, we have characterized the disease mechanisms for six LQT1 compound mutations and report that, for four of these, defective channel trafficking underlies the severe clinical phenotype.

Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: Disease mechanisms and pharmacological rescue

“…This result could be a direct consequence of the localization of the c.1781G>A mutation in the C-terminal assembly domain of the protein (13) that might affect assembly of the mutated α-subunits and, consequently, the amount of protein reaching the membrane. Our results are in agreement with a recent study in which the same mutation was overexpressed in a heterologous system and a trafficking defect was evident (30,42). In line with this mechanism, the homozygous mutation in JLNS 1781A/A -CMs caused a large reduction in I Ks , albeit not a complete loss.…”

“…5E). These data support a partial trafficking defect associated with the c.1781G>A KCNQ1 mutation, as shown in other systems (30). To better understand the consequences of the R594Q amino acid exchange in the KCNQ1 protein, we used a described in silico model (31).…”

Genome sequencing for early-onset dementia: high diagnostic yield and frequent observation of multiple contributory alleles

“…The variant is a null variant in a gene where loss-of-function is a known mechanism of disease (ACMG criterion PVS1) and is enriched in cases vs. controls with an odds ratio >5 (ACMG criterion PS4) (Kapplinger et al 2009). Furthermore, the variant’s effect is supported by well-established functional studies (Harmer et al 2014) (ACMG criterion PS3). Taken together, the presence of one very strong criterion and two strong criteria result in the ACMG-recommended assertion of “pathogenic.” Consistent with the study consent and protocol, presence of this variant was reported to the patient.…”

Lnc ing Epigenetic Control of Transcription to Cardiovascular Development and Disease

“…Thus, Kcnq1ot1 may be critical for restricting cell type expression of this important potassium ion channel in developing hearts. 122 This finding adds to the diverse chromatin regulatory mechanisms mediated by lncRNAs to control key cardiac genes and transcription factors.…”

“…Mutations in Kcnq1 perturb proper conduction in the heart, leading to congenital long QT syndrome, a cardiac disorder that manifests in varying severities of cardiac symptoms, including serious arrhythmias. 122 Biallelic expression of Kcnq1ot1 later in embryogenesis and in the postnatal heart impacts the transcription of Kcnq1, 121 whereas deletion of the noncoding transcript leads to elevated Kcnq1 levels in the heart. Interestingly, Kcnq1ot1 seems to regulate higher order chromatin interactions between an enhancer and Kcnq1.…”