Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies

Congenital long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of the QT interval and T-wave abnormalities, caused, in most cases, by mutations in KCNQ1, KCNH2, and SCN5A. Although the predominant pattern of LQTS inheritance is autosomal dominant, compound heterozygous mutations in genes encoding potassium channels have been reported, often with early disease onset and more severe phenotypes. Since the molecular mechanisms underlying severe phenotypes in carriers of compound heterozygous mutations are unknown, it is possible that these compound mutations lead to synergistic or additive alterations to channel structure and function. In this study, all-atom molecular dynamic simulations of KCNQ1 and hERG channels were carried out, including wild-type and channels with compound mutations found in two patients with severe LQTS phenotypes and limited family history of the disease. Because channels can likely incorporate different subunit combinations from different alleles, there are multiple possible configurations of ion channels in LQTS patients. This analysis allowed us to establish the structural impact of different configurations of mutant channels in the activated/open state. Our data suggest that channels with these mutations show moderate changes in folding energy (in most cases of stabilizing character) and changes in channel mobility and volume, differentiating them from each other and from WT. This would indicate possible alterations in K+ ion flow. Hetero-tetrameric mutant channels showed intermediate structural and volume alterations vis-à-vis homo-tetrameric channels. These findings support the hypothesis that hetero-tetrameric channels in patients with compound heterozygous mutations do not necessarily lead to synergistic structural alterations.

Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations

Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD.

Expanding the phenotype of SLC12A6-associated sensorimotor neuropathy

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a rare autosomal recessive condition characterised by early-onset severe progressive neuropathy, variable degrees of ACC and cognitive impairment. Mutations in SLC12A6 (solute carrier family 12, member 6) encoding the K+–Cl- transporter KCC3 have been identified as the genetic cause of HMSN/ACC. We describe fraternal twins with compound heterozygous mutations in SLC12A6 and much milder phenotype than usually described. Neither of our patients requires assistance to walk. The female twin is still running and has a normal intellect. Charcot-Marie-Tooth Examination Score 2 was 8/28 in the brother and 5/28 in the sister. Neurophysiology demonstrated a length-dependent sensorimotor neuropathy. MRI brain showed normal corpus callosum. Genetic analysis revealed compound heterozygous mutations in SLC12A6, including a whole gene deletion. These cases expand the clinical and genetic phenotype of this rare condition and highlight the importance of careful clinical phenotyping.