Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe members of 4 kindreds with a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia). By analysis of linkage we localize the putative causative gene to a 2.5-Mb segment of chromosome 1q23.2-23.3. Direct DNA sequencing of KCNJ10, which encodes an inwardly rectifying K(+) channel, identifies previously unidentified missense or nonsense mutations on both alleles in all affected subjects. These mutations alter highly conserved amino acids and are absent among control chromosomes. Many of these mutations have been shown to cause loss of function in related K(+) channels. These findings demonstrate that loss-of-function mutations in KCNJ10 cause this syndrome, which we name SeSAME. KCNJ10 is expressed in glia in the brain and spinal cord, where it is believed to take up K(+) released by neuronal repolarization, in cochlea, where it is involved in the generation of endolymph, and on the basolateral membrane in the distal nephron. We propose that KCNJ10 is required in the kidney for normal salt reabsorption in the distal convoluted tubule because of the need for K(+) recycling across the basolateral membrane to enable normal activity of the Na(+)-K(+)-ATPase; loss of this function accounts for the observed electrolyte defects. Mice deficient for KCNJ10 show a related phenotype with seizures, ataxia, and hearing loss, further supporting KCNJ10's role in this syndrome. These findings define a unique human syndrome, and establish the essential role of basolateral K(+) channels in renal electrolyte homeostasis.
 ...
PMID:Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. 1928 23

To determine the phenotypic significance of copy number changes (CNCs) in the human genome, we performed genome-wide segmental aneuploidy profiling by BAC-based array-CGH of 278 unrelated patients with multiple congenital abnormalities and mental retardation (MCAMR) and in 48 unaffected family members. In 20 patients, we found de novo CNCs composed of multiple consecutive probes. Of the 125 probes making up these probably pathogenic CNCs, 14 were also found as single CNCs in other patients and 5 in healthy individuals. Thus, these CNCs are not by themselves pathogenic. Almost one out of five patients and almost one out of six healthy individuals in our study cohort carried a gain or a loss for any one of the recently discovered microdeletion/microduplication loci, whereas seven patients and one healthy individual showed losses or gains for at least two different loci. The pathogenic burden resulting from these CNCs may be limited as they were found with similar frequencies among patients and healthy individuals (P=0.165; Fischer's exact test), and several individuals showed CNCs at multiple loci. CNCs occurring specifically in our study cohort were enriched for components of the glutamate receptor family (GRIA2, GRIA4, GRIK2 and GRIK4) and genes encoding proteins involved in guiding cell localization during development (ATP1A2, GIRK3, GRIA2, KCNJ3, KCNJ10, KCNK17 and KCNK5). This indicates that disease cohort-specific compilations of CNCs may aid in identifying loci, genes and biological processes that contribute to the phenotype of patients.
 ...
PMID:Recurrent copy number changes in mentally retarded children harbour genes involved in cellular localization and the glutamate receptor complex. 1962 14

SeSAME syndrome is a complex disease characterized by seizures, sensorineural deafness, ataxia, mental retardation and electrolyte imbalance. Mutations in the inwardly rectifying potassium channel Kir4.1 (KCNJ10 gene) have been linked to this condition. Kir4.1 channels are weakly rectifying channels expressed in glia, kidney, cochlea and possibly other tissues. We determined the electrophysiological properties of SeSAME mutant channels after expression in transfected mammalian cells. We found that a majority of mutations (R297C, C140R, R199X, T164I) resulted in complete loss of Kir4.1 channel function while two mutations (R65P and A167V) produced partial loss of function. All mutant channels were rescued upon co-transfection of wild-type Kir4.1 but not Kir5.1 channels. Cell-surface biotinylation assays indicate significant plasma membrane expression of all mutant channels with exception of the non-sense mutant R199X. These results indicate the differential loss of Kir channel function among SeSAME syndrome mutations.
 ...
PMID:Variable loss of Kir4.1 channel function in SeSAME syndrome mutations. 2067 78

The heteromeric inwardly rectifying Kir4.1/Kir5.1 K(+) channel underlies the basolateral K(+) conductance in the distal nephron and is extremely sensitive to inhibition by intracellular pH. The functional importance of Kir4.1/Kir5.1 in renal ion transport has recently been highlighted by mutations in the human Kir4.1 gene (KCNJ10) that result in seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME)/epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) syndrome, a complex disorder that includes salt wasting and hypokalemic alkalosis. Here, we investigated the role of the Kir5.1 subunit in mice with a targeted disruption of the Kir5.1 gene (Kcnj16). The Kir5.1(-/-) mice displayed hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria. The short-term responses to hydrochlorothiazide, an inhibitor of ion transport in the distal convoluted tubule (DCT), were also exaggerated, indicating excessive renal Na(+) absorption in this segment. Furthermore, chronic treatment with hydrochlorothiazide normalized urinary excretion of Na(+) and Ca(2+), and abolished acidosis in Kir5.1(-/-) mice. Finally, in contrast to WT mice, electrophysiological recording of K(+) channels in the DCT basolateral membrane of Kir5.1(-/-) mice revealed that, even though Kir5.1 is absent, there is an increased K(+) conductance caused by the decreased pH sensitivity of the remaining homomeric Kir4.1 channels. In conclusion, disruption of Kcnj16 induces a severe renal phenotype that, apart from hypokalemia, is the opposite of the phenotype seen in SeSAME/EAST syndrome. These results highlight the important role that Kir5.1 plays as a pH-sensitive regulator of salt transport in the DCT, and the implication of these results for the correct genetic diagnosis of renal tubulopathies is discussed.
 ...
PMID:Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome. 2163 11

Inwardly rectifying potassium (Kir) channels exhibit an asymmetrical conductance at hyperpolarization (high conductance) compared to depolarization (low conductance). The KCNJ10 gene which encodes an inwardly rectifying K+ channel Kir4.1 subunit plays an essential role in the inner ear and hearing. Mutations or deficiency of KCNJ10 can cause hearing loss with epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) or SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) syndromes. In this review, we mainly focus on the expression and function of Kir4.1 channels in the inner ear and mutation-induced EAST/SeSAME syndromes to provide insight for understanding the pathogenesis of deafness induced by KCNJ10 deficiency.
 ...
PMID:[EAST/SeSAME syndrome and functional expression of inward rectifier potassium channel Kir4.1 in the inner ear]. 2667 56

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.
 ...
PMID:EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients. 2972 15

Clinical, pathological, and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described and compared with its human counterpart. Based on the family history and the phenotype/genotype relationships already described in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole-exome sequencing identified the SLC12A6 NC_006612.3(XM_014109414.2): c.178_181delinsCATCTCACTCAT (p.(Met60Hisfs*14)) truncating variant. This loss-of-function variant perfectly segregated within the affected Malinois family in an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, including Malinois. In humans, SLC12A6 variants cause "agenesis of the corpus callosum with peripheral neuropathy" (ACCPN, alias Andermann syndrome), owing to a dysfunction of this K+-Cl- cotransporter. However, depending on the variant (including truncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoform described so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis of the corpus callosum nor obvious mental retardation have been observed in dogs. On the other hand, progressive spinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis, and myokymia-like muscle contractions have not been described in humans with ACCPN so far. As this is the first report of a naturally occurring disease-causing SLC12A6 variant in a non-human species, the canine model will be highly valuable to better understand the complex molecular pathophysiology of SLC12A6-related neurological disorders and to evaluate novel treatment strategies.
 ...
PMID:Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs. 3116 Jul