Potassium channels (K+-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability. Genetic variants affecting many of ...the human K+-channels are well known causes of Mendelian disorders within cardiology, neurology, and endocrinology. K+-channels are also primary targets of many natural toxins from poisonous organisms and drugs used within cardiology and metabolism. As genetic tools are improving and larger clinical samples are being investigated, the spectrum of clinical phenotypes implicated in K+-channels dysfunction is rapidly expanding, notably within immunology, neurosciences, and metabolism. K+-channels that previously were considered to be expressed in only a few organs and to have discrete physiological functions, have recently been found in multiple tissues and with new, unexpected functions. The pleiotropic functions and patterns of expression of K+-channels may provide additional therapeutic opportunities, along with new emerging challenges from off-target effects. Here we review the functions and therapeutic potential of K+-channels, with an emphasis on the nervous system, roles in neuropsychiatric disorders and their involvement in other organ systems and diseases.
•Genetic variants of human K+-channels cause cardiological, neurological, and endocrinological diseases.•Dysregulation of K+-channels is associated diabetes and neurological defects.•Targeting K+-channels as a drug target is challenging because of their critical physiological functions and risk of serious side effects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aims/hypothesis
Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust ...approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)
-
MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes.
Methods
We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped
HNF1A
variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers’ phenotype and treatment response to sulfonylurea.
Results
In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing
,
revealing 19 with
HNF1A
variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic.
Conclusions/interpretation
Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY.
Graphical Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Neonatal diabetes has been shown to be associated with high neuropsychiatric morbidity in a genotype-phenotype-dependent manner. However, the specific impact of different mutations on intellectual ...functioning is still insufficiently characterized. Specifically, only a small number of subjects with developmental delay have been comprehensively assessed, creating a knowledge gap about patients carrying the heaviest burden.
We assessed the intellectual functioning and mental health of the complete Norwegian population with K
channel neonatal diabetes. Eight sulfonylurea-treated children (five with the p.V59M genotype
) were assessed using age-matched control subjects with type 1 diabetes. The investigations included a physical and motor developmental examination, cerebral MRI, psychometrical examination, and questionnaires assessing intellectual capabilities and psychiatric morbidity.
A strong genotype-phenotype correlation was found, revealing the p.V59M genotype as highly associated with substantial intellectual disability, with no significant correlation with the time of sulfonylurea initiation. Consistent with previous studies, other genotypes were associated with minor cognitive impairment. Cerebral MRI verified normal brain anatomy in all but one child.
We here presented a comprehensive assessment of intellectual functioning in the largest cohort of p.V59M subjects to date. The level of intellectual disability revealed not only changes the interpretation of other psychological measures but downplays a strong protective effect of sulfonylurea. Within the scope of this study, we could not find evidence supporting an early treatment start to be beneficial, although a weaker effect cannot be ruled out.
OBJECTIVE
Neonatal diabetes has been shown to be associated with high neuropsychiatric morbidity in a genotype-phenotype–dependent manner. However, the specific impact of different mutations on ...intellectual functioning is still insufficiently characterized. Specifically, only a small number of subjects with developmental delay have been comprehensively assessed, creating a knowledge gap about patients carrying the heaviest burden.
RESEARCH DESIGN AND METHODS
We assessed the intellectual functioning and mental health of the complete Norwegian population with KATP channel neonatal diabetes. Eight sulfonylurea-treated children (five with the p.V59M genotype KCNJ11) were assessed using age-matched control subjects with type 1 diabetes. The investigations included a physical and motor developmental examination, cerebral MRI, psychometrical examination, and questionnaires assessing intellectual capabilities and psychiatric morbidity.
RESULTS
A strong genotype-phenotype correlation was found, revealing the p.V59M genotype as highly associated with substantial intellectual disability, with no significant correlation with the time of sulfonylurea initiation. Consistent with previous studies, other genotypes were associated with minor cognitive impairment. Cerebral MRI verified normal brain anatomy in all but one child.
CONCLUSIONS
We here presented a comprehensive assessment of intellectual functioning in the largest cohort of p.V59M subjects to date. The level of intellectual disability revealed not only changes the interpretation of other psychological measures but downplays a strong protective effect of sulfonylurea. Within the scope of this study, we could not find evidence supporting an early treatment start to be beneficial, although a weaker effect cannot be ruled out.
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