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BACKGROUND: KCNJ10 and CAPN1 variants cause "spinocerebellar" ataxia in dogs, but their association with generalized myokymia and neuromyotonia remains unclear. OBJECTIVE: To investigate the association between KCNJ10 and CAPN1 and myokymia or neuromyotonia, with or without concurrent spinocerebellar ataxia. ANIMALS: Thirty-three client-owned dogs with spinocerebellar ataxia, myokymia neuromytonia, or a combination of these signs. METHODS: Genetic analysis of a cohort of dogs clinically diagnosed with spinocerebellar ataxia, myokymia or neuromyotonia. KCNJ10 c.627C>G and CAPN1 c.344G>A variants and the coding sequence of KCNA1, KCNA2, KCNA6, KCNJ10 and HINT1 were sequenced using DNA extracted from blood samples. RESULTS: Twenty-four Jack Russell terriers, 1 Jack Russell terrier cross, 1 Dachshund and 1 mixed breed with spinocerebellar ataxia were biallelic (homozygous) for the KCNJ10 c.627C>G variant. Twenty-one of those dogs had myokymia, neuromyotonia, or both. One Parson Russell terrier with spinocerebellar ataxia alone was biallelic for the CAPN1 c.344G>A variant. Neither variant was found in 1 Jack Russell terrier with ataxia alone, nor in 3 Jack Russell terriers and 1 Yorkshire terrier with myokymia and neuromyotonia alone. No other causal variants were found in the coding sequence of the investigated candidate genes in these latter 5 dogs. CONCLUSION: The KCNJ10 c.627C>G variant, or rarely the CAPN1 c.344G>A variant, was confirmed to be the causal variant of spinocerebellar ataxia. We also report the presence of the KCNJ10 c.627C>G variant in the Dachshund breed. In dogs with myokymia and neuromyotonia alone the reported gene variants were not found. Other genetic or immune-mediated causes should be investigated to explain the clinical signs of these cases.
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Enfermedades de los Perros , Síndrome de Isaacs , Miocimia , Ataxias Espinocerebelosas , Humanos , Perros , Animales , Miocimia/genética , Miocimia/veterinaria , Síndrome de Isaacs/genética , Síndrome de Isaacs/veterinaria , Ataxias Espinocerebelosas/veterinaria , Ataxia/veterinaria , Cruzamiento , Proteínas del Tejido Nervioso , Canal de Potasio Kv1.6 , Enfermedades de los Perros/genéticaRESUMEN
Renal tubules play an important role in maintaining water, electrolyte, and acid-base balance. Renal tubule dysfunction can cause electrolyte disorders and acid-base imbalance. Clinically, hypokalemic renal tubular disease is the most common tubule disorder. With the development of molecular genetics and gene sequencing technology, hereditary renal tubular diseases have attracted attention, and an increasing number of pathogenic genes related to renal tubular diseases have been discovered and reported. Inherited renal tubular diseases mainly occur due to mutations in genes encoding various specific transporters or ion channels expressed on the tubular epithelial membrane, leading to dysfunctional renal tubular reabsorption, secretion, and excretion. An in-depth understanding of the molecular genetic basis of hereditary renal tubular disease will help to understand the physiological function of renal tubules, the mechanism by which the kidney maintains water, electrolyte, and acid-base balance, and the relationship between the kidney and other systems in the body. Meanwhile, understanding these diseases also improves our understanding of the pathogenesis of hypokalemia, alkalosis and other related diseases and ultimately promotes accurate diagnostics and effective disease treatment. The present review summarizes the most common hereditary renal tubular diseases (Bartter syndrome, Gitelman syndrome, EAST syndrome and Liddle syndrome) characterized by hypokalemia and alkalosis. Further detailed explanations are provided for pathogenic genes and functional proteins, clinical manifestations, intrinsic relationship between genotype and clinical phenotype, diagnostic clues, differential diagnosis, and treatment strategies for these diseases.
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Alcalosis , Síndrome de Bartter , Hipopotasemia , Enfermedades Renales , Humanos , Hipopotasemia/etiología , Hipopotasemia/genética , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Síndrome de Bartter/terapia , Enfermedades Renales/complicaciones , Alcalosis/diagnóstico , Alcalosis/genética , Alcalosis/terapia , AguaRESUMEN
The inwardly rectifying potassium channel (Kir) 4.1 (encoded by KCNJ10) interacts with Kir5.1 (encoded by KCNJ16) to form a major basolateral K+ channel in the renal distal convoluted tubule (DCT), connecting tubule (CNT), and the cortical collecting duct (CCD). Kir4.1/Kir5.1 heterotetramer plays an important role in regulating Na+ and K+ transport in the DCT, CNT, and CCD. A recent development in the field has firmly established the role of Kir4.1/Kir5.1 heterotetramer of the DCT in the regulation of thiazide-sensitive Na-Cl cotransporter (NCC). Changes in Kir4.1/Kir5.1 activity of the DCT are an essential step for the regulation of NCC expression/activity induced by dietary K+ and Na+ intakes and play a role in modulating NCC by type 2 angiotensin II receptor (AT2R), bradykinin type II receptor (BK2R), and ß-adrenergic receptor. Since NCC activity determines the Na+ delivery rate to the aldosterone-sensitive distal nephron (ASDN), a distal nephron segment from late DCT to CCD, Kir4.1/Kir5.1 activity plays a critical role not only in the regulation of renal Na+ absorption but also in modulating renal K+ excretion and maintaining K+ homeostasis. Thus, Kir4.1/Kir5.1 activity serves as an important component of renal K+ sensing mechanism. The main focus of this review is to provide an overview regarding the role of Kir4.1 and Kir5.1 of the DCT and CCD in the regulation of renal K+ excretion and Na+ absorption.
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Canales de Potasio de Rectificación Interna , Túbulos Renales , Túbulos Renales Distales , Potenciales de la Membrana , Nefronas , Canales de Potasio de Rectificación Interna/genética , SodioRESUMEN
In 2009, two groups independently linked human mutations in the inwardly rectifying K+ channel Kir4.1 (gene name KCNJ10) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na+, K+, and Mg2+ with urine, activation of the renin-angiotensin-aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (KCNJ16). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.
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Epidemiological and clinical observations have shown that potassium ingestion is inversely correlated with arterial hypertension prevalence and cardiovascular mortality. The higher the dietary potassium, the lower the blood pressure and mortality. This phenomenon is explained, at least in part, by the interaction between salt reabsorption in the distal convoluted tubule (DCT) and potassium secretion in the connecting tubule/collecting duct of the mammalian nephron: In order to achieve adequate K+ secretion levels under certain conditions, salt reabsorption in the DCT must be reduced. Because salt handling by the kidney constitutes the basis for the long-term regulation of blood pressure, losing salt prevents hypertension. Here, we discuss how the study of inherited diseases in which salt reabsorption in the DCT is affected has revealed the molecular players, including membrane transporters and channels, kinases, and ubiquitin ligases that form the potassium sensing mechanism of the DCT and the processes through which the consequent adjustments in salt reabsorption are achieved.
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Hipertensión , Túbulos Renales Distales , Animales , Presión Sanguínea , Homeostasis , PotasioRESUMEN
Evolution moves in mysterious ways. Excretion of waste products by glomerular filtration made perfect sense when life evolved in the ocean. Yet, the associated loss of water and solutes became a problem when life moved onto land: a serious design change was needed and this occurred in the form of ever more powerful tubules that attached to the glomerulus. By reabsorbing typically more than 99% of the glomerular filtrate, the tubules not only minimise urinary losses, but, crucially, also maintain homeostasis: tubular reabsorption and secretion are adjusted so as to maintain an overall balance, in which urine volume and composition matches intake and environmental stressors. A whole orchestra of highly specialised tubular transport proteins is involved in this process and dysfunction of one or more of these results in the so-called kidney tubulopathies, characterised by specific patterns of clinical and biochemical abnormalities. In turn, recognition of these patterns helps establish a specific diagnosis and pinpoints the defective transport pathway. In this review, we will discuss these clinical and biochemical "fingerprints" of tubular disorders of salt-handling and how sodium handling affects volume homeostasis but also handling of other solutes.
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Enfermedades Renales , Riñón , Humanos , Glomérulos Renales , Cloruro de Sodio , Cloruro de Sodio DietéticoRESUMEN
KCNJ10 encodes the inward-rectifying potassium channel (Kir4.1) that is expressed in the brain, inner ear, and kidney. Loss-of-function mutations in KCNJ10 gene cause a complex syndrome consisting of epilepsy, ataxia, intellectual disability, sensorineural deafness, and tubulopathy (EAST/SeSAME syndrome). Patients with EAST/SeSAME syndrome display renal salt wasting and electrolyte imbalance that resemble the clinical features of impaired distal tubular salt transport in Gitelman's syndrome. A key distinguishing feature between these two conditions is the additional neurological (extrarenal) manifestations found in EAST/SeSAME syndrome. Recent reports have further expanded the clinical and mutational spectrum of KCNJ10-related disorders including non-syndromic early-onset cerebellar ataxia. Here, we describe a kindred of three affected siblings with early-onset ataxia, deafness, and progressive spasticity without other prominent clinical features. By using targeted next-generation sequencing, we have identified two novel missense variants, c.488G>A (p.G163D) and c.512G>A (p.R171Q), in the KCNJ10 gene that, in compound heterozygosis, cause this distinctive EAST/SeSAME phenotype in our family. Electrophysiological characterization of these two variants confirmed their pathogenicity. When expressed in CHO cells, the R171Q mutation resulted in 50% reduction of currents compared to wild-type KCNJ10 and G163D showed a complete loss of function. Co-expression of G163D and R171Q had a more pronounced effect on currents and membrane potential than R171Q alone but less severe than single expression of G163D. Moreover, the effect of the mutations seemed less pronounced in the presence of Kir5.1 (encoded by KCNJ16), with whom the renal Kir4.1 channels form heteromers. This partial functional rescue by co-expression with Kir5.1 might explain the lack of renal symptoms in the patients. This report illustrates that a spectrum of disorders with distinct clinical symptoms may result from mutations in different parts of KCNJ10, a gene initially associated only with the EAST/SeSAME syndrome.
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Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Mutación Missense , Canales de Potasio de Rectificación Interna/genética , Convulsiones/genética , Anciano , Animales , Células CHO , Cricetulus , Femenino , Pérdida Auditiva Sensorineural/fisiopatología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/fisiopatología , Persona de Mediana Edad , Linaje , Fenotipo , Convulsiones/fisiopatologíaRESUMEN
Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution.
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Síndrome de Bartter/clasificación , Canales de Cloruro/genética , Síndrome de Gitelman/clasificación , Sodio/metabolismo , Síndrome de Bartter/genética , Síndrome de Bartter/patología , Canales de Cloruro/metabolismo , Síndrome de Gitelman/genética , Síndrome de Gitelman/patología , Humanos , Túbulos Renales Distales/patología , Asa de la Nefrona/patología , Mutación , Reabsorción Renal/genéticaRESUMEN
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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OBJECTIVE: EAST syndrome comprises of epilepsy, ataxia, sensorineural deafness, and tubulopathy. It is caused by a mutation in KCNJ10 gene. Less than thirty cases have been reported in the literature with emphasis on genetic mutation and renal tubulopathy. In this article, our goal is to present a comprehensive description of epilepsy and its management. A literature review is also presented to consolidate and compare our findings with the previously reported cases. METHODS: Retrospective chart review was done to collect patient data. Research clinic was organized to obtain missing data. Molecular genetic testing was done at the CGC Genetics Laboratory. Electroencephalogram (EEG) was done for all patients and interpreted by a pediatric epileptologist and brain MRI was reviewed by a pediatric neuroradiologist. Developmental assessment was done by a developmental pediatrician using Griffiths Mental Developmental Scale. RESULTS: In patients with EAST syndrome, seizure is the first symptom occurring around 3-4â¯months of age. Most common seizure type was generalized tonic clonic (GTC). Usually, the seizures were brief lasting <3â¯min but few patients also presented with status epilepticus especially when the medication was weaned. Carbamazepine (CBZ) was found to be effective in most cases. Lamotrigine (LTG), valproic acid (VPA), and topiramate (TPM) were also found to be helpful. Routine EEGs were usually normal or showed non-specific findings. In few patients, EEG showed background slowing. Brain MRI revealed hyperintensity in the dentate nuclei in some patients, and quantitative volumetric analysis studies showed volume loss in different regions of the brain especially the cerebellum. All our five patients have the same homozygous c.170C>T (p.Thr57Ile) missense mutation in KCNJ10 gene. CONCLUSION: This article provides the readers with an understanding of the natural history of epilepsy in this syndrome to help in early recognition, avoid unnecessary investigations, and provide the best treatment for seizures. It also helps the physicians to share the prognosis of this rare syndrome with the parents.
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Epilepsia/genética , Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Canales de Potasio de Rectificación Interna/genética , Convulsiones/genética , Anticonvulsivantes/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Carbamazepina/uso terapéutico , Ataxia Cerebelosa/tratamiento farmacológico , Niño , Preescolar , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Femenino , Pérdida Auditiva Sensorineural/complicaciones , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Masculino , Mutación/genética , Mutación Missense/genética , Linaje , Canales de Potasio de Rectificación Interna/metabolismo , Estudios Retrospectivos , Convulsiones/complicaciones , Convulsiones/tratamiento farmacológico , Síndrome , Ácido Valproico/uso terapéuticoRESUMEN
EAST (Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy) or SeSAME (Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance) syndrome is a rare autosomal recessive syndrome first described in 2009 independently by Bockenhauer and Scholl. It is caused by mutations in KCNJ10, which encodes Kir4.1, an inwardly rectifying K+ channel found in the brain, inner ear, kidney and eye. To date, 16 mutations and at least 28 patients have been reported. In this paper, we review mutations causing EAST/SeSAME syndrome, clinical manifestations in detail, and efficacy of treatment in previously reported patients. We also report a new Latvian kindred with 4 patients. In contrast to the majority of previous reports, we found a progressive course of the disorder in terms of hearing impairment and neurologic deficit. The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices. Future research should concentrate on recognizing the lesions in the central nervous system to evaluate new potential diagnostic criteria and on formally evaluating intellectual disability.
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Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Canales de Potasio de Rectificación Interna/genética , Convulsiones/genética , Encéfalo/anomalías , Oído Interno/anomalías , Anomalías del Ojo/genética , Pérdida Auditiva Sensorineural/epidemiología , Humanos , Discapacidad Intelectual/epidemiología , Riñón/anomalías , Letonia/epidemiología , Mutación , Fenotipo , Convulsiones/epidemiologíaRESUMEN
BACKGROUND: Epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) is a rare channelopathy due to KCNJ10 mutations. So far, only mild cerebellar hypoplasia and/or dentate nuclei abnormalities have been reported as major neuroimaging findings in these patients. METHODS: We analyzed the clinical and brain MRI features of two unrelated patients (aged 27 and 23 years) with EAST syndrome carrying novel homozygous frameshift mutations (p.Asn232Glnfs*14and p.Gly275Valfs*7) in KCNJ10, detected by whole exome sequencing. RESULTS: Brain MRI examinations at 8 years in Patient 1 and at 13 years in Patient 2 revealed a peculiar brain and spinal cord involvement characterized by restricted diffusion of globi pallidi, thalami, brainstem, dentate nuclei, and cervical spinal cord in keeping with intramyelinic edema. The follow-up studies, performed, respectively, after 19 and 10 years, showed mild cerebellar atrophy and slight progression of the brain and spinal cord T2 signal abnormalities with increase of the restricted diffusion in the affected regions. CONCLUSION: The present cases harboring novel homozygous frameshift mutations in KCNJ10 expand the spectrum of brain abnormalities in EAST syndrome, including mild cerebellar atrophy and intramyelinic edema, resulting from abnormal function of the Kir4.1 inwardly rectifying potassium channel at the astrocyte endfeet, with disruption of water-ion homeostasis.
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Mutación del Sistema de Lectura , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/genética , Canales de Potasio de Rectificación Interna/genética , Convulsiones/diagnóstico por imagen , Convulsiones/genética , Sustancia Blanca/diagnóstico por imagen , Adulto , Atrofia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Progresión de la Enfermedad , Humanos , Masculino , Médula Espinal/diagnóstico por imagen , Médula Espinal/patología , Sustancia Blanca/patología , Adulto JovenRESUMEN
Mutations in KCNJ10, which encodes the inwardly rectifying potassium channel Kir4.1, a primary regulator of membrane excitability and potassium homeostasis, cause a complex syndrome characterized by seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance called SeSAME/EAST syndrome. We describe a 41-year-old patient with non-syndromic, slowly progressive, early-onset ataxia. Targeted next-generation sequencing identified a novel c.180 T > G (p.Ile60Met) missense homozygous mutation. The mutated residue Ile60Met likely impairs phosphatidylinositol 4, 5-bisphosphate (PIP2) binding which is known to play an essential role in channel gating. Our study expands the clinical and mutational spectrum of KCNJ10-related disorders and suggests that screening of this gene should be implemented in patients with early-onset ataxia, with or without syndromic features.
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Mutación Missense , Canales de Potasio de Rectificación Interna/genética , Degeneraciones Espinocerebelosas/genética , Adulto , Secuencia de Aminoácidos , Femenino , Homocigoto , Humanos , Modelos Moleculares , Fenotipo , Canales de Potasio de Rectificación Interna/metabolismo , Degeneraciones Espinocerebelosas/diagnóstico por imagen , Degeneraciones Espinocerebelosas/fisiopatologíaRESUMEN
Kir4.1 in the distal convoluted tubule plays a key role in sensing plasma potassium and in modulating the thiazide-sensitive sodium-chloride cotransporter (NCC). Here we tested whether dietary potassium intake modulates Kir4.1 and whether this is essential for mediating the effect of potassium diet on NCC. High potassium intake inhibited the basolateral 40 pS potassium channel (a Kir4.1/5.1 heterotetramer) in the distal convoluted tubule, decreased basolateral potassium conductance, and depolarized the distal convoluted tubule membrane in Kcnj10flox/flox mice, herein referred to as control mice. In contrast, low potassium intake activated Kir4.1, increased potassium currents, and hyperpolarized the distal convoluted tubule membrane. These effects of dietary potassium intake on the basolateral potassium conductance and membrane potential in the distal convoluted tubule were completely absent in inducible kidney-specific Kir4.1 knockout mice. Furthermore, high potassium intake decreased, whereas low potassium intake increased the abundance of NCC expression only in the control but not in kidney-specific Kir4.1 knockout mice. Renal clearance studies demonstrated that low potassium augmented, while high potassium diminished, hydrochlorothiazide-induced natriuresis in control mice. Disruption of Kir4.1 significantly increased basal urinary sodium excretion but it abolished the natriuretic effect of hydrochlorothiazide. Finally, hypokalemia and metabolic alkalosis in kidney-specific Kir4.1 knockout mice were exacerbated by potassium restriction and only partially corrected by a high-potassium diet. Thus, Kir4.1 plays an essential role in mediating the effect of dietary potassium intake on NCC activity and potassium homeostasis.
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Túbulos Renales Distales/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Potasio en la Dieta/metabolismo , Alcalosis/genética , Alcalosis/metabolismo , Alcalosis/fisiopatología , Animales , Modelos Animales de Enfermedad , Femenino , Homeostasis , Hidroclorotiazida/farmacología , Hipopotasemia/genética , Hipopotasemia/metabolismo , Hipopotasemia/fisiopatología , Túbulos Renales Distales/efectos de los fármacos , Túbulos Renales Distales/fisiopatología , Masculino , Potenciales de la Membrana , Ratones Noqueados , Natriuresis , Canales de Potasio de Rectificación Interna/deficiencia , Canales de Potasio de Rectificación Interna/genética , Eliminación Renal , Sodio/orina , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Canal Kir5.1RESUMEN
We report a consanguineous family with three affected siblings with novel mutation in the KCNJ10 gene. All three presented with central nervous system symptoms in the form of infantile focal seizures, ataxia, slurred speech with early developmental delay and intellectual disability in two siblings. None had any associated electrolyte abnormalities and no symptomatic hearing deficits were observed.
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Ataxia/genética , Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Mutación Missense/genética , Canales de Potasio de Rectificación Interna/genética , Convulsiones/genética , Adolescente , Edad de Inicio , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Masculino , Linaje , Hermanos , Adulto JovenRESUMEN
Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a â¼1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in the KCNJ10 gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in KCNJ10 were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider KCNJ10:c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population. These dogs represent an animal model for the human EAST syndrome.
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Enfermedad de Canavan/genética , Ataxia Cerebelosa/genética , Ligamiento Genético , Canales de Potasio de Rectificación Interna/genética , Animales , Cruzamiento , Enfermedad de Canavan/fisiopatología , Enfermedad de Canavan/veterinaria , Ataxia Cerebelosa/fisiopatología , Ataxia Cerebelosa/veterinaria , Perros , Heterogeneidad Genética , Haplotipos , HumanosRESUMEN
EAST syndrome is a recently described autosomal recessive disorder secondary to mutations in KCNJ10 (Kir4.1), a gene encoding a potassium channel expressed in the brain, eye, ear and kidney. This condition is characterized by 4 cardinal features; Epilepsy, Ataxia, Sensorineural deafness, and (a renal salt-wasting) Tubulopathy, hence the acronym EAST syndrome. Here we review reported clinical manifestations, in particular the neurological signs and symptoms which typically have the most impact on the quality of life of patients. In addition we review the pathophysiology and genetic aspects of the disease. So far 14 different KCNJ10 mutations have been published which either directly affect channel function or may lead to mislocalisation. Investigations of the pathophysiology may provide clues to potential treatments.
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Kcnj10 encodes the inwardly rectifying K(+) channel 4.1 (Kir4.1) and is expressed in the basolateral membrane of late thick ascending limb, distal convoluted tubule (DCT), connecting tubule (CNT), and cortical collecting duct (CCD). In the present study, we perform experiments in postneonatal day 9 Kcnj10(-/-) or wild-type mice to examine the role of Kir.4.1 in contributing to the basolateral K(+) conductance in the CNT and CCD, and to investigate whether the disruption of Kir4.1 upregulates the expression of the epithelial Na(+) channel (ENaC). Immunostaining shows that Kir4.1 is expressed in the basolateral membrane of CNT and CCD. Patch-clamp studies detect three types of K(+) channels (23, 40, and 60 pS) in the basolateral membrane of late CNT and initial CCD in wild-type (WT) mice. However, only 23- and 60-pS K(+) channels but not the 40-pS K(+) channel were detected in Kcnj10(-/-) mice, suggesting that Kir.4.1 is a key component of the 40-pS K(+) channel in the CNT/CCD. Moreover, the depletion of Kir.4.1 did not increase the probability of finding the 23- and 60-pS K(+) channel in the CNT/CCD. We next used the perforated whole cell recording to measure the K(+) reversal voltage in the CNT/CCD as an index of cell membrane potential. Under control conditions, the K(+) reversal potential was -69 mV in WT mice and -61 mV in Kcnj10(-/-) mice, suggesting that Kir4.1 partially participates in generating membrane potential in the CNT/CCD. Western blotting and immunostaining showed that the expression of ENaCß and ENaCγ subunits from a renal medulla section of Kcnj10(-/-) mice was significantly increased compared with that of WT mice. Also, the disruption of Kir4.1 increased aquaporin 2 expression. We conclude that Kir4.1 is expressed in the CNT and CCD and partially participates in generating the cell membrane potential. Also, increased ENaC expression in medullary CD of Kcnj10(-/-) mice is a compensatory action in response to the impaired Na(+) transport in the DCT.
Asunto(s)
Canales Epiteliales de Sodio/metabolismo , Túbulos Renales Colectores/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Animales , Potenciales de la Membrana , Ratones , Regulación hacia ArribaRESUMEN
The renal phenotype induced by loss-of-function mutations of inwardly rectifying potassium channel (Kir), Kcnj10 (Kir4.1), includes salt wasting, hypomagnesemia, metabolic alkalosis and hypokalemia. However, the mechanism by which Kir.4.1 mutations cause the tubulopathy is not completely understood. Here we demonstrate that Kcnj10 is a main contributor to the basolateral K conductance in the early distal convoluted tubule (DCT1) and determines the expression of the apical Na-Cl cotransporter (NCC) in the DCT. Immunostaining demonstrated Kcnj10 and Kcnj16 were expressed in the basolateral membrane of DCT, and patch-clamp studies detected a 40-pS K channel in the basolateral membrane of the DCT1 of p8/p10 wild-type Kcnj10(+/+) mice (WT). This 40-pS K channel is absent in homozygous Kcnj10(-/-) (knockout) mice. The disruption of Kcnj10 almost completely eliminated the basolateral K conductance and decreased the negativity of the cell membrane potential in DCT1. Moreover, the lack of Kcnj10 decreased the basolateral Cl conductance, inhibited the expression of Ste20-related proline-alanine-rich kinase and diminished the apical NCC expression in DCT. We conclude that Kcnj10 plays a dominant role in determining the basolateral K conductance and membrane potential of DCT1 and that the basolateral K channel activity in the DCT determines the apical NCC expression possibly through a Ste20-related proline-alanine-rich kinase-dependent mechanism.