Novel mutation in the <i>KCNJ10</i> gene in three siblings with seizures, ataxia and no electrolyte abnormalities

Dhaibani, Muna A. Al; El‐Hattab, Ayman W.; Holroyd, Kathryn B.; Orthmann-Murphy, Jennifer; Larson, Valerie A; Siddiqui, Khurram A; Szólics, Miklós; Schiess, Nicoline

doi:10.1080/01677063.2017.1404057

Cited by 13 publications

(9 citation statements)

References 20 publications

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“…However, the two affected siblings described in this study exhibited only infantile onset of seizures and delayed fine motor ability, with no apparent hearing impairment or electrolyte disturbances. Our findings are in accordance with a recent study in which three siblings with a homozygous Kir4.1 mutation (I60T) were reported to present with seizures, ataxia, and no electrolyte or hearing abnormalities (Al Dhaibani et al, 2018). Similarly, in Jack Russell Terriers, naturally occurring Kir4.1 variants (I209M and L329P) cause marked spinocerebellar ataxia and epilepsy without any effect on electrolyte balance or hearing (Rohdin et al, 2015; Van Poucke et al, 2017).…”

Section: Discussionsupporting

confidence: 93%

“…To date, approximately 20 different pathogenic variations of KCNJ10 have been reported. Most of the patients harbor homozygous or compound heterozygous mutations, while other types of mutations (e.g., nonsense) are rare (Bockenhauer et al, 2009; Scholl et al, 2009; Reichold et al, 2010; Freudenthal et al, 2011; Scholl et al, 2012; Kara et al, 2013; Papavasiliou et al, 2017;Abdelhadi et al, 2016;Al Dhaibani et al, 2018;Nicita et al, 2018). Herein, we report two novel variants of KCNJ10 in a compound heterozygous state in two siblings who manifest epilepsy and motor delays, two cardinal symptoms of SeSAME/EAST syndrome.…”

Section: Introductionmentioning

confidence: 99%

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Novel KCNJ10 Compound Heterozygous Mutations Causing EAST/SeSAME-Like Syndrome Compromise Potassium Channel Function

et al. 2019

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Inwardly rectifying K+ channel 4.1 (Kir4.1), encoded by KCNJ10, is a member of the inwardly rectifying potassium channel family. In the brain, Kir4.1 is predominant in astrocytic glia and accounts for the spatial buffering of K+ released by neurons during action potential propagation. A number of studies have shown that mutations in KCNJ10 are associated with SeSAME/EAST syndrome, which is characterized by seizures, ataxia, sensorineural deafness, and electrolyte imbalance. Herein, we identified two siblings presenting with seizures and motor delays in one outbred kindred. Customized targeted-exome sequencing showed that both affected siblings are compound heterozygous for two KCNJ10 missense mutations (NM_002241.4: c.601G > A: p.A201T and c.626T > C: p.I209T). Prediction tools suggested that both amino acid substitutions were deleterious or disease causing. Further functional studies showed that Chinese hamster ovary (CHO) cells expressing either A201T and/or I209T Kir4.1 channels exhibited lower K+ currents, indicating compromised Kir4.1 biological function. Intriguingly, the A201T but not I209T mutation decreased total and cell surface Kir4.1 levels. Kir4.1 channels with the A201T mutation were unstable and degraded through lysosomal pathway. In conclusion, these data indicated that both A201T and I209T mutations disrupt Kir4.1 activity and are the cause of SeSAME/EAST-like syndrome in the siblings.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Novel KCNJ10 Compound Heterozygous Mutations Causing EAST/SeSAME-Like Syndrome Compromise Potassium Channel Function

et al. 2019

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“…Other missense mutations including Ala201Thr and/ or Ile209Thr and Ile60Thr, despite an earlier time of presentation than patient 1 and 2 (before 7m/o), were associated with milder neurologic phenotypes compared to our truncating mutations (25,26). Finally, no signs of tubulopathy and hearing loss were diagnosed up to 3 y/o in patients with the Ala201Thr and/or Ile209Thr mutations and up to 20 y/o in patients carrying the Ile60Thr mutation.…”

Section: Symptoms Severitymentioning

confidence: 65%

A case series of adult patients affected by EAST/SeSAME syndrome suggests more severe disease in subjects bearing <i>KCNJ10</i> truncating mutations

Suzumoto

Columbano

Gervasi

et al. 2021

IRDR

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Kir4.1, potassium channel, tubulopathy EAST/SeSAME syndrome is a rare disease affecting the Central Nervous System (CNS), inner ear, and kidney. The syndrome is due to loss-of-function mutations in the KCNJ10 gene encoding the inward-rectifying potassium channel Kir4.1. EAST/SeSAME syndrome is mainly diagnosed during childhood with a tonic-clonic seizure being the usual first symptom. Due to a limited number of patients and recent identification of the disease, few data are available on the clinical progress of this disease in adulthood. In particular, neurologic and nephrological outcomes have not been reported. We present a case series of 4 adult patients harbouring homozygous missense mutation p.Ala167Val and homozygous frameshift mutations p.Asn232Glnfs * 14 and p.Gly275Valfs * 7. Effects of these mutations were predicted by in silico modelling and bioinformatic tools. Patients with truncating mutations were associated with more severe outcomes, both in tubulopathy severity and neurological symptomatology. Conversely, either missense or truncating mutations were correlated with similar severity of epilepsy, with a long free-of-event period up to 20 years old. No eGFR decline was documented. Modelling predicted that truncating mutations lead to complete Kir4.1 dysfunction. Finally, all patients had a mild increase in urinary protein excretion. Our study indicates that the prognosis of patients suffering from EAST/SeSAME syndrome is related to the severity of the mutation causing the disease. As predicted by in silico modelling, truncating mutations of KCNJ10 are associated with more severe disease, with recurrence of symptomatic hypokalemia and more severe neurological phenotype. The type of mutation should be considered for the therapy tailored to patients' phenotype.

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“…All six affected individuals in SeSAME family reported here displayed relatively uniform neurological and psychiatric manifestations in the form of ataxia, focal epilepsy, delayed developmental milestones, loss of intellectual and sensory-neural hearing but with no apparent electrolyte imbalance. These clinical features specific to SeSAME-like pedigrees (Dhaibani et al, 2018) is also evident in children with autism-spectrum disorders with epilepsy (Sicca et al, 2011;Sicca et al, 2016). In fact, several modern-day mammals like Jack Russell Terriers (Gilliam et al, 2014), Belgian Shepherd dogs (Mauri et al, 2017) and Malinois dogs (Van Poucke et al, 2017) experienced this SeSAME-like phenotype with KCNJ10 mutations.…”

Section: Why Renal Tubulopathy Is Spared In a Subset Of Sesame Cases?mentioning

confidence: 95%

Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance

Nadella¹,

Chellappa²,

Subramaniam³

et al. 2018

Preprint

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Novel mutation in the KCNJ10 gene in three siblings with seizures, ataxia and no electrolyte abnormalities

Cited by 13 publications

References 20 publications

Novel KCNJ10 Compound Heterozygous Mutations Causing EAST/SeSAME-Like Syndrome Compromise Potassium Channel Function

Novel KCNJ10 Compound Heterozygous Mutations Causing EAST/SeSAME-Like Syndrome Compromise Potassium Channel Function

A case series of adult patients affected by EAST/SeSAME syndrome suggests more severe disease in subjects bearing <i>KCNJ10</i> truncating mutations

Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance

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