De Novo Mutations in SIK1 Cause a Spectrum of Developmental Epilepsies

Abstract

Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, these results expand the genetic etiologies of developmental epilepsies by demonstrating SIK1 mutations as a cause of severe developmental epilepsy.

Haploinsufficiency of autism spectrum disorder candidate gene NUAK1 impairs cortical development and behavior in mice

“…Many of the AMPK-RKs are enriched in the developing brain and several have been linked to neurodevelopmental disorders. For example, mutations in Sik1 have been identified in patients suffering from developmental epilepsy 35 , and polymorphisms in Mark1 are associated with an increased risk for ASD 36 . AMPK-RKs might have partially overlapping functions: for example the simultaneous inactivation of the polarity kinases BRSK1 (SAD-B) and BRSK2 (SAD-A) is required to disrupt axon specification in mouse cortical neurons yet Brsk1 ; Brsk2 double KO is lethal shortly after birth 12 , whereas single gene inactivation is less phenotypic and viable.…”

Autism spectrum disorder and epileptic encephalopathy: common causes, many questions

“…In a cohort of 7 patients with SLC6A1 variants underlying myoclonic-atonic epilepsy, 5 (71%) had “autistic features,” mild-severe ID (along with regression in 2 individuals), and a full spectrum of seizure types [ 29 ]. Other disorders with relatively high rates of ASD features alongside epileptic encephalopathy include HCN1 -related epilepsy (67% [ 30 ]) and SIK1 -related epilepsy (50% [ 31 ]). HCN1 mutations affect hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels which regulate pacemaker currents in neurons, resulting in an early infantile epileptic encephalopathy with characteristics of DS initially followed later by the emergence of atypical absences, ID, and ASD features [ 30 ].…”

Comprehensive Analysis of Tissue-wide Gene Expression and Phenotype Data Reveals Tissues Affected in Rare Genetic Disorders

“…For instance, Salt-Inducible Kinase 1 ( SIK1 , OMIM ID: 605705) is expressed at its highest level in skin and the lowest in brain. Yet mutations in SIK1 lead to severe developmental epilepsy without a known skin phenotype (Hansen et al, 2015). HNRNPDL associated with Limb-Girdle Muscular Dystrophy (OMIM ID: 609115) has lower expression in skeletal muscle than most other tissues (see the Genotype-Tissue Expression Project (GTEx) portal for gene expression levels across tissues).…”