Loss-of-Function Alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect

AbstractAutosomal recessive hypophosphatemic rickets 2 (ARHR2) is a rare form of renal tubular phosphate wasting disorder. Loss of function mutations of the ecto-nucleotide pyrophosphatase/pyrophosphodiesterase 1 gene (

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A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

Journal of Neurology ◽

10.1007/s00415-021-10524-7 ◽

2021 ◽

Author(s):

David Mengel ◽

Andreas Traschütz ◽

Selina Reich ◽

Alejandra Leyva-Gutiérrez ◽

Friedemann Bender ◽

...

Keyword(s):

Early Onset ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

De Novo ◽

Family Members ◽

Start Codon ◽

Mrna Levels ◽

Adult Onset ◽

Loss Of Function ◽

Autosomal Dominant Disorder

Abstract Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.

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Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy

Journal of Human Genetics ◽

10.1038/jhg.2014.103 ◽

2014 ◽

Vol 60 (2) ◽

pp. 97-101 ◽

Cited By ~ 18

Author(s):

Hirofumi Kodera ◽

Hitoshi Osaka ◽

Mizue Iai ◽

Noriko Aida ◽

Akio Yamashita ◽

...

Keyword(s):

Early Onset ◽

Trna Synthetase ◽

Epileptic Encephalopathy

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A KCNQ2 variant causing Early Onset Epileptic Encephalopathy increases spontaneous network-driven activity and excitability of pyramidal cells in the layer II/III and V of the motor cortex during a limited period of development

10.1101/2020.05.12.090464 ◽

2020 ◽

Author(s):

Najoua Biba ◽

Marie Kurz ◽

Laurent Villard ◽

Mathieu Milh ◽

Hélène Becq ◽

...

Keyword(s):

Early Onset ◽

Pyramidal Cells ◽

Epileptic Encephalopathy ◽

Synaptic Activity ◽

Loss Of Function ◽

Electrophysiological Properties ◽

Layer V ◽

The Impact ◽

Cortical Slices ◽

Limited Period

SummaryDe novo variants in the KCNQ2 gene encoding the Kv7.2 subunit of the voltage-gated potassium Kv7/M channel are the main cause of Early Onset Epileptic Encephalopathy (EOEE) with suppression burst suggesting that this channel plays an important role for proper brain development. Functional analysis of these variants in heterologous cells has shown that most of them are loss of function leading to a reduction of M current. However the cellular mechanism of the neuronal network dysfunctionning is still not known. Here we characterized the electrophysiological properties of developing pyramidal cells of the layer II/III and V and analyzed spontaneous synaptic activity in these layers in motor cortical slices obtained from a recently generated heterozygous knock-in mouse harboring the loss-of-function pathogenic p.T274M variant. Experiments were performed on animals aged one week, three weeks and four-five weeks, and the results were compared with those of pyramidal cells recorded in slices from wild-type mice untreated or treated with the Kv7 channel blocker XE-991. We showed that the variant led to a hyperexcitability of pyramidal cells of layer II/III in cortical slices from animal aged 1 week and 3 weeks and to a level that was similar to the effect of XE-911. In layer V the impact of the variant was observed in slices from animal aged 3 weeks but not earlier and to a level that was lower to the effect of XE-991. However, in cortical slices from animal aged 4-5 weeks electrophysiological properties of pyramidal cells of layers II/III and V were no more affected by the variant but still sensitive to XE-991. The recovery of the electrophysiological responses in knock-in animals was associated with a slight but significant distal shift of the axonal initial segment (AIS) from the soma of pyramidal cells of layer II/III and V. Recordings of spontaneous synaptic activity in these layers revealed the presence of recurrent GABAergic network activities (RGNA) that were mainly observed during the three first postnatal weeks of life and which occurrence and frequency were increased in pyramidal cells of the layer II/III but not of the layer V of the knock-in mouse. There were no significant differences in synaptic activities mediated by GABA and glutamate receptors in cortical slices from animal aged 4-5 weeks. Together our data provided evidences that the heterozygous p.T274M variant impacts the activity of pyramidal cells and probably of Gabaergic interneurons during a limited period of development. Our data also indicated that neurons of the layer II/III are more sensitive to the variant than those located in the layer V in terms of age of onset, neuronal firing and spontaneous synaptic activities. Moreover our data suggest that a compensatory mechanism might take place in the knock-in mice aged 4-5 weeks allowing the recovery of control activity at cellular and network levels and which is associated with a slight displacement of the AIS. Thus, the effect of the variant on neuronal activity is developmentally regulated and is reminiscent to some characteristics of KCNQ2-related EOEE.

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Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

Journal of Pediatric Genetics ◽

10.1055/s-0040-1721077 ◽

2020 ◽

Author(s):

Yousef Binamer ◽

Muzamil A. Chisti

Keyword(s):

Autosomal Recessive ◽

Common Mechanism ◽

Sequencing Analysis ◽

Loss Of Function ◽

Skin Atrophy ◽

Whole Exome ◽

Infancy And Childhood ◽

Genetics And Genomics ◽

New Feature ◽

Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

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