Splicing Characterization of CLCNKB Variants in Four Patients With Type III Bartter Syndrome

Wang, Chunli; Han, Yanming; Zhou, Jiaran; Zheng, Bixia; Zhou, Wei; Bao, Huaying; Jia, Zhanjun; Huang, Songming; Ding, Guofu; Zhao, Fei

doi:10.3389/fgene.2020.00081

Cited by 20 publications

(14 citation statements)

References 22 publications

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“…Written informed consent was obtained from the proband’s parents for the publication of any potentially identifiable images or data included in this article. The method of WES was mentioned in the previous report [ 13 ]. All genetic variants were screened and listed in Table S1: Additional file 1 .…”

Section: Case Presentationmentioning

confidence: 99%

Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report

Zhang

et al. 2021

BMC Pediatr

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Background The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl−/H+ exchanger ClC-4 prominently expressed in brain. Case presentation We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. Conclusion Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family.

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Section: Case Presentationmentioning

confidence: 99%

Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report

Zhang

et al. 2021

BMC Pediatr

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“…The parents refused to do the muscle biopsy and electromyogram (EMG) but accepted the whole exome sequencing (WES). The method of WES was mentioned in our previous report [6]. To verify the mutated point, we amplified the segments carrying the mutations.…”

Section: Case Presentationmentioning

confidence: 99%

A rare case of pediatric recurrent rhabdomyolysis with compound heterogenous variants in the LPIN1

et al. 2020

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Background Lipin-1, encoded by LPIN1 gene, serves as an enzyme and a transcriptional co-regulator to regulate lipid metabolism and mitochondrial respiratory chain. Autosomal recessive mutations in LPIN1 were recognized as one of the most common causes of pediatric recurrent rhabdomyolysis in western countries. However, to date, there were only a few cases reported in Asian group. This study aims to report the first pediatric case of recurrent rhabdomyolysis with a novel LPIN1 mutation in China mainland in order to raise the awareness of both pediatricians and patients. Case presentations Here we report a Chinese pediatric case of recurrent rhabdomyolysis with compound heterozygous variants (p.Arg388* and p.Arg810Cys) in the LPIN1 gene. The c.2428C > T was a novel missense variant involved Arg-to-Cys substitution at position 810 (p.Arg810Cys), located in the highly conserved region which predicted to be damaging by multiple algorithms. The patient manifested as cola-colored urine, muscle weakness and tenderness, as well as acute kidney injury with peak blood creatine kinase level 109,570 U/l in 19-month old. In his second episode of 9 years old, the symtoms were relatively milder with peak creatine kinase level 50,948 U/l. He enjoyed quite normal life between the bouts but slightly elevation of serum creatine kinase level during the fever or long-term exercises. Prolonged weight training combined with calorie deprivation were speculated to be the triggers of his illness. Prompt symptomatic therapy including fluid therapy and nutritional support was given and the patient recovered soon. Conclusions LPIN1-related rhabdomyolysis is still quite new to physicians due to its seemly low-incidence especially in Asian countries. In the future, more active genetic test strategy and detailed prophylactic care education should be taken in patients with severe recurrent rhabdomyolysis, who are the high risk group of LPIN1 genetic defects.

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“…Generally, exonic point variants are classified as missense, synonymous, silent, or non-sense variants, and certain point variants cause abnormal precursor-mRNA (pre-mRNA) splicing, a key step in gene expression, and this has been associated to the pathogenesis of various disorders (Takeuchi et al, 2015;Gonzalez-Paredes et al, 2016;Shao et al, 2018;Han et al, 2019;Wang et al, 2020). The pre-mRNA splicing process can be changed by point variants, which disrupt canonical splice sites (5 donor site, 3 acceptor site and branch site) and polypyrimidine tract (Gonzalez-Paredes et al, 2014; or creating or deactivating sequences that regulate splicing, such as exonic splicing enhancers/silencers (ESEs/ESSs) or intronic splicing enhancers/silencers (ISEs/ISSs) (Cartegni et al, 2002;Gonzalez-Paredes et al, 2014;Takeuchi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay

Wang

Liu

et al. 2020

Front. Genet.

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Background: Familial renal glucosuria is a rare renal tubular disorder caused by SLC5A2 gene variants. Most of them are exonic variants and have been classified as missense variants. However, there is growing evidence that some of these variants can be detrimental by affecting the pre-mRNA splicing process. Therefore, we hypothesize that a certain proportion of SLC5A2 exonic variants can result in disease via interfering with the normal splicing process of the pre-mRNA. Methods: We used bioinformatics programs to analyze 77 previously described presumed SLC5A2 missense variants and identified candidate variants that may alter the splicing of pre-mRNA through minigene assays. Results: Our study indicated six of 7 candidate variants induced splicing alterations. Variants c.216C > A, c.294C > A, c.886G > C, c.932A > G and c.962A > G may disrupt splicing enhancer motifs and generate splicing silencer sequences resulting in the skipping of exon 3. Variants c.305C > T and c.1129G > A probably disturb splice sites leading to exon skipping. Conclusion: To our knowledge, we report, for the first time, SLC5A2 exonic variants that produce alterations in pre-mRNA. Our research reinforces the importance of assessing the consequences for putative point variants at the mRNA level. Additionally, we propose that minigenes function analysis may be valuable to evaluate the impact of SLC5A2 exonic variants on pre-mRNA splicing without patients' RNA samples.

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Splicing Characterization of CLCNKB Variants in Four Patients With Type III Bartter Syndrome

Cited by 20 publications

References 22 publications

Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report

Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report

A rare case of pediatric recurrent rhabdomyolysis with compound heterogenous variants in the LPIN1

Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay

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