Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.1). Patch-clamp recordings showed strong negative shifts in voltage-dependent activation for all but one KCNH1 channel mutant (Gly469Arg). Coexpression of Gly469Arg with wild-type KCNH1 resulted in heterotetrameric channels with reduced conductance at positive potentials but pronounced conductance at negative potentials. These data support a gain-of-function effect for all ZLS-associated KCNH1 mutants. We also identified a recurrent de novo missense change in ATP6V1B2, encoding the B2 subunit of the multimeric vacuolar H(+) ATPase, in two individuals with ZLS. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Our findings demonstrate that KCNH1 mutations cause ZLS and document genetic heterogeneity for this disorder.

SummaryBackgroundDeafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.MethodsThrough a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.Findings26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.InterpretationOur findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.FundingUS National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

Aim. KCNH1 mutations have been identified in patients with Zimmermann‐Laband syndrome and Temple‐Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Methods. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Results. Epilepsy was present in 7/9 patients. Both generalized and focal tonic‐clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Conclusions. Epilepsy is a key phenotypic feature in most individuals with KCNH1‐related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.

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COVID-19 patients have a higher risk of developing inflammatory responses associated with serious and even fatal respiratory diseases. The role of oxidative stress in exacerbating manifestations in COVID-19 pathogenesis is under-reported.This study aimed touseserum levels of superoxide dismutase (SOD3) and glutathione-S-transferase (GSTp1) by ELISA, zinc (ErbaChem5), ferritin and free iron (VitrosChemistry, Ortho Clinical Diagnosis, Raritan, NJ, USA) at the first encounter of randomly selected RT-PCR-positive COVID-19 patients, for assessing disease severity. The parameters which helped in identifying the severity, leading to poor prognosis, were neutrophil:lymphocyte higher than 4, high CRP, low SOD3 values and high GSTp1 values, and diabetes mellitus as a co-morbidity. Higher zinc levels correlated with high GSTp1 and low SOD3, indicating the protective effect of zinc on ROS. The increased high GSTp1 shows an anticipated protective biochemical response, to mitigate the low SOD3 values due to ROS consumption. Decreased SOD3 levels indicate a state of high oxidative stress at cellular levels, and an anticipated increase in GSTp1 levels points to the pathophysiological bases of increasing severity with age, sex, and co-morbidities, such asdiabetes. High levels of initial GSTp1 and zinc levels possibly offer protection to redox reactions at the cellular level in severe COVID-19 infection, preventing deterioration.