Mutations In SLC26A4 Gene Research Articles

The clinical feature of glucose transporter 1 deficiency syndrome and literature review

Objective To investigate the clinical features of glucose transporter 1 deficiency syndrome(GLUT1-DS) and summarize the characteristics of GLUT1-DS through reviewing related references. Methods The clinical data including manifestation, cerebrospinal fluid(CSF) glucose, electroencephalogram, MRI and gene mutation of a patient with GLUT1-DS was collected and the related literatures were reviewed. Results The patient was a 6 years old boy.The patient, whose seizures occurred at the age of 9 month-old and prolonged to 6 year-old, attacked before breakfast.Physical examination showed microcephaly with head circumference 47.5 cm.Laboratory tests showed that CSF glucose decreased(1.87 mmol/L) and CSF-serum ratio was 0.36.And meantime the MRI was normal and electroencephalogram showed general spike and slow wave complex paroxysm.Mutation of SLC2A1 gene, c.350_385del, was found in the patient.There were 219 cases with GLUT1-DS had been reported and the age of onset was 15.69 months.In 219 patients, 159 cases(72%)suffered seizures, 105 cases(47%) had motor abnormalities, 61 cases(27%) suffered intellectual disability.The CSF glucose values were(1.92±0.31) mmol/L, CSF-serum ratio was 0.36±0.07.SLC2A1 gene mutations were detected in 183 patients(96%)in which missense mutation was the most mutation. Conclusion A wide range of phenotypes of GLUT1-DS include seizures, motor abnormalities, mental retardation.The diagnosis is confirmed when CSF glucose and CSF-serum ratio are continuously decreased which in the absence of meningitis.The SLC2A1 gene should be detected in suspicion of GLUTI-DS patients.Early diagnosis and treatment may improve the prognosis of those GLUTI-DS patients. Key words: Glucose transporter 1 deficiency syndrome; SLC2A1 gene; Seizures; Motor abnormalities

Identification of a novel mutation in SLC26A4 gene in a Chinese family with enlarged vestibular aqueduct syndrome

ObjectiveTo investigate the genetic causes of hearing loss in a two generation Chinese family with enlarged vestibular aqueduct syndrome (EVAS). MethodsClinical and genetic evaluations were conducted in a deaf proband and her normal-hearing parents. Sanger sequencing analysis of all the 21 exons, the exon–intron boundaries and the promoter in SLC26A4 gene was performed to detect the pathogenic mutations. PCR-restricted fragment length polymorphism (PCR-RFLP) was used to further identify the mutation. Phylogenetic analysis was carried out with multiple sequence alignment using BioEdit software. Three-dimensional (3D) modeling of the human wild-type and mutant SLC26A4 (NP_000432.1) was carried out using I-TASSER (http://zhanglab.ccmb.med.umich.edu/). ResultsClinical examinations showed that the proband suffered from typical features of sensorineural hearing loss with enlarged vestibular aqueduct. A novel nonsense mutation c.2118C>A (p.C706X) in exon 19 was identified in compound heterozygosity with the splice-site mutation c.919-2A>G in the proband by using Sanger sequencing. The mother was a heterozygous carrier of c.919-2A>G in intron 7, while the father was a heterozygous carrier of c.2118C>A. The mutation c.2118C>A was not found in 200 unrelated controls using Sanger sequencing. PCR-RFLP showed the PCR product of the proband was not digested at 2110 by Fau I because of the c.2118C>A mutation. 3D-structure modeling indicated that the mutation c.2118C>A resulted in a truncate Pendrin protein. Protein alignment indicated high conservation of p.C706 residue in healthy Homo, Nomascus, Pan, Macaca, Canis, Sus, Mus, Rattus, Cricetulus and Xenopus. ConclusionsThis study revealed a novel heterozygous mutation c.2118C>A (p.C706X) compound with c.919-2A>G in SLC26A4 gene in a patient with EVAS.

Generalized Lipoathrophy: A New Phenotype of H-Syndrome

The H-syndrome is a recently known autosomal recessive genodermatosis caused by mutations in the SLC29A3 gene, which encodes the nucleoside transporter hENT3. Cutaneous changes including Hyper pigmentation, hypertrichosis is characteristic for this syndrome but herein, we newly describe this syndrome in a 16 years old boy associated with generalized lipoatrophy and a novel mutation in exon 3 G155>A mutation in SLC29A3 gene. It seems that the clinical spectrum of this syndrome is much broader than the symptoms which were described in the first reported patients.

GLUT-1 deficiency: From pathophysilogy and genetics to abroad clinical spectrum

The classical GLUT-1 deficiency syndrome (GLUT-1 DS, De Vivo disease) was described over 2 decades ago as a metabolic encephalopathy characterized by developmental delay, secondary microcephaly paroxysmal neurological symptoms (epilepsy) and movement disorders. The biochemical parameters of this disease, used in diagnosis, are low levels of glucose in the cerebrospinal fluid, normal level of glucose in the blood and consequent low ratio of cerebrospinal fluid vs. blood glucose levels (<40-45%). So far, more than 200 cases of the classical GLUT-1 DS have been described in the literature. Genetic research demonstrated that this disease is caused by mutations in SLC2A1 gene coding for GLUT-1, a transporter of glucose across the blood brain barrier. Over the last few years the clinical spectrum of GLUT-1 deficiencywas expanded to include other rare diseases such as paroxysmal exertional dyskinesia and early-onset absence epilepsy, but also some more common diseases such as idiopathic generalised epilepsy (1-2%). GLUT-1 deficiency is an important pathophysiological basis of these diseases as early diagnosis (aided by DNA mutation testing) and treatment (ketogenic diet) could lead to improved disease outcomes.

Novel nonsense mutation (p.Ile411Metfs*12) in the SLC19A2 gene causing Thiamine Responsive Megaloblastic Anemia in an Indian patient

Thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive disorder, is caused by mutations in SLC19A2 gene encodes a high affinity thiamine transporter (THTR-1). The occurrence of TRMA is diagnosed by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Here, we report a female TRMA patient of Indian descent born to 4th degree consanguineous parents presented with retinitis pigmentosa and vision impairment, who had a novel homozygous mutation (c.1232delT/ter422; p.Ile411Metfs*12) in 5th exon of SLC19A2 gene that causes premature termination of hTHTR-1. PROSITE analysis predicted to abrogate GPCRs family-1 signature motif in the variant by this mutation c.1232delT/ter422, suggesting uncharacteristic rhodopsin function leading to cause RP clinically. Thiamine transport activity by the clinical variant was severely inhibited than wild-type THTR-1. Confocal imaging had shown that the variant p.I411Mfs*12 is targeted to the cell membrane and showed no discrepancy in membrane expression than wild-type. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of hTHTR-1 causing TRMA in an Indian patient through functionally impaired thiamine transporter activity.

Clinical characteristics and SLC12A3 gene mutation analysis of a patient with Gitelman syndrome

Clinical characteristics and SLC12A3 gene mutation analysis of a patient with Gitelman syndrome

AB089. Postnatal and prenatal diagnosis for neonatal intrahepatic cholestasis caused by citrin deficiency

Background and objective Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) which resulted from mutation in SLC25A13 gene can present transient intrahepatic cholestasis, low birth weight, growth retardation, hypoproteinemia, prolong jaundice, chronic liver disease and so on. This study aimed to identify mutations of SLC25A13 for 649 NICCD and 46 siblings, from September 2009 to December 2014 and prenatal diagnosis for pregnancies with high risk of NICCD.

Normomagnesemic Gitelman Syndrome Patients Exhibit A Stronger Reaction to Thiazide than Hypomagnesemic Patients

In recent decades, the thiazide test has been introduced to aid the diagnosis of Gitelman syndrome (GS), but the effect of thiazide in normomagnesemic GS patients is currently unknown. This study was conducted to compare the thiazide test results of normomagnesemic and hypomagnesemic GS patients. Seventeen GS patients with SLC12A3 gene mutations were enrolled, five of whom did not have a history of hypomagnesemia. The clinical data were documented, and SLC12A3 gene screening was performed. The thiazide test was performed in all of the patients and 20 healthy controls. A receiver operating characteristic curve was used to evaluate the sensitivity and specificity of the thiazide test in the diagnosis of GS. A 7-fold increase in sodium and chloride excretion was observed after thiazide application in healthy controls, and an approximately 2-fold increase was found in the 5 normomagnesemic GS patients; however, there was no change in the 12 hypomagnesemic GS patients. A weaker reaction to thiazide was observed in hypomagnesemic compared with normomagnesemic GS patients. The clearance of chloride in 1 patient was overestimated because of chronic renal function insufficiency (CRI). When a reasonable cutoff value for chloride fractional excretion was selected, the thiazide test was 95% sensitive and 94.1% specific for the diagnosis of GS. Hypomagnesemic GS patients exhibited greater sodium-chloride cotransporter dysfunction than normomagnesemic GS patients. When CRI occurs, the chloride and sodium clearance rates, rather than the fractional excretion, should be used in the evaluation of the thiazide test results.

Spectrum and frequency of GJB2, GJB6 and SLC26A4 gene mutations among nonsyndromic hearing loss patients in eastern part of India

Genetically caused nonsyndromic hearing loss is highly heterogeneous. Inspite of this large heterogeneity, mutations in the genes GJB2, GJB6 and SLC26A4 are major contributors. The mutation spectrum of these genes varies among different ethnic groups. Only a handful of studies focused on the altered genetic signature of these genes in different demographic regions of India but never focused on the eastern part of the country. Our study for the first time aimed to characterize the mutation profile of these genes in hearing loss patients of West Bengal state, India. Mutations in GJB2, GJB6 and SLC26A4 genes were screened by bidirectional sequencing from 215 congenital nonsyndromic hearing loss patients. Radiological diagnosis was performed in patients with SLC26A4 mutations by temporal bone CT scan. The study revealed that 4.65% and 6.97% patients had monoallelic and biallelic GJB2 mutations respectively. Six mutations were identified, p.W24X being the most frequent one accounting for 71.05% of the mutated alleles. Mutations in GJB6 including the previously identified deletion mutation (GJB6-D13S1830) were not identified in our study. Further, no patients harbored biallelic mutations in the SLC26A4 gene or the common inner ear malformation Enlarged Vestibular Aqueduct (EVA). The mutation profile of GJB2 in our study is distinct from other parts of India, suggesting that the mutation spectrum of this gene varies with ethnicity and geographical origin. The absence of GJB6 mutations and low frequency of SLC26A4 mutations suggest that additional genetic factors may also contribute to this disease.

A Novel Mutation of SCL26A4 gene in Turkish Family with Pendred Syndrome

Aim: This study aimed to investigate the molecular testing of congenital hearing loss by using next generation sequencing technology. Pendred syndrome (PS) is described by severe bilateral sensorineural hearing loss with goiter. The mutations of SCL26A4 gene can cause PS. Material and Method: We evaluated the feasibility of target-enrichment and massive parallel sequencing technologies to interrogate all mutations of genes (GJB2, GJB3, GJB6, SLC26A4 and for the mitochondrial mutation A1555G) implicated in NSHL, we performed molecular analyses of 14 NSHL families and patients by using Miseq system (Illumina Inc.). Next-Generation sequencing (NGS) technologies provide specificity, sensitivity and reproducibility at levels sufficient to perform genetic diagnosis of hearing loss. Results: We found two different mutations in SCL26A4 gene such as F354S and I588T in both consanguineous families as diagnosed with Pendred syndrome and we reported a novel mutation in SCL26A4 gene. We found no mutation in GJB2, GJB3, GJB6 gene and A1555G mtDNA in this study. Conclusion: These results highlight the benefits using targeted gene panels with NGS technologies in the molecular analysis of nonsyndromic, congenital hearing loss patients. This study assessed the frequency of deafness genes in Turkish children with congenital hearing loss who had been treated with cochlear implantation, and we found a novel mutation (I588T) in SLC26A4 gene. Key Words: Pendred syndrome, Congenital Hearing Loss, Next-Generation sequencing

Transmembrane protein 139 (TMEM139) interacts with human kidney isoform of anion exchanger 1 (kAE1)

Human kidney anion exchanger 1 (kAE1) mediates Cl−/HCO3− exchanges at the basolateral membrane of the acid-secreting α-intercalated cells. Mutations in SLC4A1 gene encoding kAE1 are associated with distal renal tubular acidosis (dRTA). Several studies have shown that impaired trafficking of the mutant kAE1 is an important molecular mechanism underlying the pathogenesis of dRTA. Proteins involved in kAE1 trafficking were identified but the mechanism resulting in dRTA remained unclear. Thus, this study attempted to search for additional proteins interacting with C-terminal of kAE1 (Ct-kAE1) and involved in kAE1 trafficking to cell membrane. Transmembrane protein 139 (TMEM139) was identified as a protein interacting with Ct-kAE1 by yeast two-hybrid screening. The interaction between kAE1 and TMEM139 was confirmed by affinity co-purification, co-immunoprecipitation (co-IP) and yellow fluorescent protein (YFP)-based protein fragment complementation assay (PCA). In addition, flow cytometry results showed that suppression of endogenous TMEM139 by small interfering RNA (siRNA) and over-expression of TMEM139 in HEK293T cells could reduce and increase membrane localization of kAE1, respectively. The presented data demonstrate that TMEM139 interacts with kAE1 and promotes its intracellular trafficking.

Clinical characteristics and SLC12A3 gene mutation profile of Gitelman syndrome: One case report

Objective To describe the clinical characteristics of a patient with Gitelman syndrome, and to identify the associated SLC12A3 gene mutations. Methods A suspected case of teenager-onset Gitelman syndrome was observed in our hospital. It was further confirmed by clinical manifestations and auxiliary examination. In addition, direct sequencing for the exons of SLC12A3 gene and CLCNKB gene region was conducted to identify the probable disease-associated mutations. Results The case showed characteristics of hypokalemia, hypomagnesemia, and low level of urinary calcium and onset by age of 18. By excluding the possibilities of long-term use of thiazide diuretics, laxatives, chronic vomiting and diarrhea, he was finally diagnosed as a case of Gitelman syndrome. Furthermore, by Sanger direct sequencing, 2 coding variations were identified in SLC12A3 gene region, including T304M and L488P. L488P was a new heterozygous mutation. Conclusion Detection of SLC12A3 gene mutation could facilitate the diagnosis of Gitelman syndrome and improve prognosis. (Chin J Endocrinol Metab, 2015, 31: 438-442) Key words: Gitelman syndrome; SLC12A3; Genetic diagnosis

P94 – 2991: GLUT1-DS presenting as movement disorder in a male adolescent: Possible effect of late treatment with MAD

Glucose transporter-1 deficiency syndrome (GLUT1-DS, OMIM 606777) is a treatable hereditary disorder of brain energy metabolism caused by heterozygous mutation in SLC2A1 gene on chromosome 1p34. Resulting deficient GLUT1 protein is responsible for impaired GLUT-1 mediated glucose transport into the brain clinically leading to a wide range of neurological symptoms. We report on a 15 years old male with genetically confirmed glucose transporter type 1 deficiency syndrome (GLUT1-DS; DYT9/DYT18). Developmental delay was already present before two years of age. Sudden episodes of exercise induced weakness without loss of consciousness were assumed to be myoclonic astatic epilepsy or atypical absences and therefore treated with valproinic acid and later with ethosuximide, both ineffectively. Hypoglycorrhachia and decreased CSF to blood glucose ratio found at the age of 14 years finally led to subsequent direct sequencing of SLC2A1 gene. Standard treatment in GLUT1-DS is ketogenic diet. Modified Atkins Diet (MAD) is an alternative ketogenic diet with the advantages preserving acceptable nutrition and obtaining compliance in adolescent patients. MAD has been described to improve movement disorder, seizures, alertness, cognitive abilities, and electroencephalography findings in GLUT1-DS in children. In our adolescent patient MAD was initiated in January 2015 to ameliorate symptoms such as movement disorder, paroxysmal exercise-induced dyskinesia, hypokinesia, tremor, rigor, spasticity and intellectual disability. In spite of abnormal EEG findings, symptomatic epilepsy has never been the leading symptom in this patient. We assume that even late treatment initiation of MAD in this adolescent patient could ameliorate movement disorder, cognitive function and EEG findings. Presenting this case report we will discuss actual literature concerning ketogenic diet in GLUT1-DS.

Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review.

The mutation spectrum of the GJB2 and SLC26A4 genes, the 2 most common genes causing deafness, are known to be ethnic specific. In this study, the spectrum of the reported GJB2 and SLC26A4 mutations in different populations are reviewed and considered from a human migration perspective. Fifty-two and 17 articles on GJB2 and SLC26A4 mutations, respectively, were reviewed through the PubMed database from April 1996 to September 2014. The 4 most prevalent mutations were selected and compared. A cluster analysis was subsequently performed for these selected mutations. The present review of frequent mutations shows the ethnic-specific GJB2 and SLC26A4 gene mutation spectrum. A cluster analysis of the GJB2 and SLC26A4 genes revealed similarities between ethnic populations. The mutation spectrum reviewed in this study clearly indicated that the frequent mutations in the GJB2 and SLC26A4 genes are consistent with the founder mutation hypothesis. A comparison with the Y-chromosome phylogenetic tree indicated that these mutations may have occurred during human migration.

Clinical Variability of GLUT1DS.

Investigators from Pavia, Rho, Brescia and Milan, Italy, studied 22 patients diagnosed with GLUT1 deficiency syndrome (GLUT1DS) to document clinical or genetic differences between patients with familial SLC2A1 gene mutations (n=11) and those with sporadic mutations (n=11).

GJB2 as Well as SLC26A4 Gene Mutations are Prominent Causes for Congenital Deafness.

Mutations in gap junction proteins encoding beta connexions are believed to be a major cause for congenital hearing loss. The purpose of this study was to do comparative analyses of frequencies of most prominent mutations responsible for congenital deafness. Using fluorescence PCR method, the entire coding region of GJB2 gene, GJB3 gene, and SLC26A4 was analyzed. Direct DNA sequencing was used to analyze mutations in these genes among unrelated 2,674 cases of newborns. Also, 12S rRNA mutation was also studied in these cases. In 2,674 cases of newborns from June 2013 to June 2014, found deafness mutation in 137 cases (5.12% of carrier rate), carrying GJB2 mutations in 68 cases (2.54% of carry rate), GJB3 mutations in 10 cases (0.37% of carry rate), SLC26A4 mutations in 54 cases (2.02% of carry rate), and mitochondrial 12S rRNA mutations in five cases (0.19% of carry rate). The study concludes that GJB2 gene mutation is the most common and mitochondrial 12S rRNA mutations are the least common mutation for congenital hearing loss in Chinese newborns.

Identification of a novel mutation of PJVK in the Chinese non-syndromic hearing loss population with low prevalence of the PJVK mutations

Conclusion: To our knowledge, this is the first report of PJVK gene mutation in a Chinese non-syndromic sensorineural hearing loss (NSHL) family. Our data indicate that the PJVK gene contributes to hearing impairment in the Chinese population, but it is not a major cause. Objective: To investigate the contribution of PJVK mutations to NSHL in the Chinese population. Methods: We screened for the PJVK gene in a sample of 65 autosomal recessive NSHL families without GJB2, SLC26A4, or mitochondrial 12S rRNA gene mutations. Seven pairs of PCR primers were designed to amplify all of the exons and their flanking regions of the PJVK gene. The PCR products were sequenced and analyzed for identification of mutations. Results: In all, we identified one novel frameshift mutation, c.930_931del AC (p.C312W fsX19), co-segregating with the phenotype in one consanguineous family with a prevalence of 1.5% (1/65). The p.C312W fsX19 mutation was just positioned in the zinc-fingers domain, which was important to the function of pejvakin, and resulted in a stop codon after 19 additional amino acids. It was not identified in the controls and was considered as the causative mutation of family 804566 with autosomal recessive, non-syndromic, prelingual sensorineural hearing impairment.

Analysis of genetic mutations in Chinese patients with systemic primary carnitine deficiency

Systemic primary carnitine deficiency (CDSP) is caused by mutations in SLC22A5 gene, which encodes organic cation transporter 2(OCTN2). CDSP leads to skeletal or cardiac myopathy and hepatic encephalopathy. The present study aimed to identify SLC22A5 gene mutations and analyze the potential relationship between genotype and clinical symptoms in 20 Chinese patients with CDSP. The complete coding region of the SLC22A5 gene including intron-exon boundaries were amplified and sequenced in all patients. Eighteen different mutations were found; of which, nine were novel. The mutations clustering in exons 1 and 4 accounted for 66.7% of all mutant alleles (26/39). The c.760C>T (p. R254X) was the most frequent mutation (25.6%, 10/39), suggesting it as an ethnic founder mutation. The relationship between genotype and phenotype was investigated in patients carrying the R254X mutation. Homozygous patients with R254X were late-onset cases who presented with dilated cardiomyopathy and muscle weakness after 1 year of age. Compound heterozygous patients carrying R254X, combined with other missense mutations occurred in very specific positions, dramatically altered OCTN2 protein function. Based on the analysis of case studies, a clear relationship between free carnitine (C0) level in plasma and OCTN2 genotype was not found in the present work, however, the low plasma C0 level could not indicate disease severity or genotype. Further functional studies with a large sample size are required to understand the relationship between R254X mutation and CDSP.

Analysis of common deafness gene mutations in deaf people from unique ethnic groups in Gansu Province, China

Conclusions: The GJB2 gene mutation characteristic of Dongxiang was the interaction result of ethnic background and geographical environment, and Yugur exhibited the typical founder effect. The SLC26A4 gene mutation characteristic of Dongxiang was related to caucasian backgrounds and selection of purpose exons, i.e. ethnic background and the penetrance of ethnic specificity caused the low mtDNA1555A>G mutation frequency in Dongxiang. Objectives: To determine the prevalence of GJB2 and SLC26A4 genes and mtDNA1555A>G mutations and analyze the ethnic specificity in the non-syndromic sensorineural hearing loss (NSHL) of unique ethnic groups in Gansu Province. Methods: Peripheral blood samples were obtained from Dongxiang, Yugur, Bonan, and ethnic Han groups with moderately severe to profound NSHL in Gansu Province. Bidirectional sequencing (or enzyme digestion) was applied to identify the sequence variations. Results: The pathogenic allele frequency of the three gene mutations was different. The frequency of the GJB2 gene among the Dongxiang, Yugur, Bonan, and ethnic Han groups was 9.03%, 12.5%, 5.88%, and 12.17%, respectively. No difference was found between the ethnic groups. The frequencies of the SLC26A4 genes were 3.23%, 8.33%, 0%, and 9.81%, respectively. The mutation frequency of mtDNA1555A>G was 0%, 0%, 0%, and 6.03%, respectively. No difference was found between the ethnic groups, except for the Dongxiang and ethnic Han groups, both in SLC26A4 gene and mtDNA1555A>G.

Gitelman syndrome DD thiazide diuretics abuse

Abstract Introduction. Gitelman syndrome (GS) is a rare inherited disorder. Mutations in SLC12A3 gene that encode tubular Na+Cl-cotransporter (NCCT) cause hypokalemic metabolic alkalosis, salt loss, hypomagnesaemia and hypocalciuria. The symptoms include weakness, vertigo, hypotension, tetany, paresthesia and nausea. Diagnostic criteria are a normal urine concentrating ability, normal glomerular filtration rate (GFR), hypomagnesaemia (&lt;0,65mmol/l), hypokalemia (&lt;3,6mmol/l) and hypocalciuria (&lt;0,1mmol/mmol creatinine). Previously, the diagnosis was made by exclusion. Today, genetic analysis can ensure diagnosis. Thiazide diuretics (TD) abuse with similar abnormalities can make the differential diagnosis difficult. Causal therapy of GS does not exist. The substitution of potassium and magnesium are therapeutic strategies. Case presentation. A 41-year-old obese woman presented at the emergency department with recurrent episodes of hypokalemia with concomitant weakness, muscle cramps, polyuria and collapse. The results of laboratory testing of blood and urine led to the suspected diagnosis of GS. In the follow-up examinations, the results were inconsistent. Therefore, a transient thiazide diuretics abuse was assumed. Discussion. This case demonstrates the difficulties in making the diagnosis of GS on the basis of only clinical and laboratory tests, without the use of genetic analysis. The differentiation between GS and thiazide diuretic abuse is especially difficult.