Clinical features, <i>BTD</i> gene mutations, and their functional studies of eight symptomatic patients with biotinidase deficiency from Southern China

Liu, Zongcai; Zhao, Xiaoyuan; Sheng, Huiying; Cai, Yamei; Xi, Yin; Chen, Xiaodan; Ling, Su; Lu, Zhikun; Zeng, Chunhua; Li, Xiuzhen; Liu, Li

doi:10.1002/ajmg.a.38601

Cited by 12 publications

(11 citation statements)

References 32 publications

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“…This is consistent with Wolf et al's study conducted in the United States of America (USA), whereas one patient was found to have a c.1361A>C (p.Tyr454Cys) mutation with a complete absence of the biotinidase activity (0.0 nmol/min/mL) [22]. The last detected mutation in our cohort was c.235C>T (p.Arg79Cys) in exon 2, which is common in different populations from South China [23], Iran [24], Poland [25], Turkey [17,26,27], United States [22], and Sweden [28]. The Iranian, Turkish, and American children were found to have an enzyme activity of 0.11, 0.13, and 0.0 nmol/min/mL, respectively [22,24,26].…”

Section: Discussionsupporting

confidence: 93%

Identification and Characterization of BTD Gene Mutations in Jordanian Children with Biotinidase Deficiency

AL-Eitan

Alqa'qa'

Amayreh

et al. 2020

JPM

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Biotinidase deficiency is an autosomal recessive metabolic disorder whose diagnosis currently depends on clinical symptoms and a biotinidase enzyme assay. This study aimed to investigate the mutational status and enzymatic activity of biotinidase deficiency in seven unrelated Jordanian families including 10 patients and 17 healthy family members. Amplified DNA was analyzed by the automated Sanger sequencing method, and the enzymatic assay was performed using a colorimetric assessment. Biotinidase level was significantly lower (p < 0.001) in BTD children compare to their non-affected family members. Genetic sequencing revealed six different mutations in Jordanian patients. One mutation was novel and located in exon 4, which could be a prevalent mutation for biotinidase deficiency in the Jordanian population. Identification of these common mutations and combing the enzymatic activity with genotypic data will help clinicians with regard to better genetic counseling and management through implementing prevention programs in the future.

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Section: Discussionsupporting

confidence: 93%

Identification and Characterization of BTD Gene Mutations in Jordanian Children with Biotinidase Deficiency

AL-Eitan

Alqa'qa'

Amayreh

et al. 2020

JPM

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“…BTD encodes the biotinidase protein, which recycles protein-bound biotin by cleaving biotin (biotinepsilon-lysine) that is a normal product of carboxylase degradation, resulting in regeneration of free biotin [24]. BTD-deficiency is associated with various diseases [25]. In our current study, we found that BTD was downregulated in iCCA, and was positively associated with the OS of iCCA patients.…”

Section: Discussionsupporting

confidence: 53%

Identification of a Three-gene Signature Acting as a Novel Prognostic Biomarker in Intrahepatic Cholangiocarcinoma Patients

Tang¹,

Hunag²,

Li³

et al. 2020

Preprint

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Background: Intrahepatic cholangiocarcinoma (iCCA) patients have poor outcomes due to the lack of biomarkers for the selection of treatment options. The present study was conducted to find biomarkers with independent prognostic vaule in iCCA patients. Methods: Gene transcriptome profiles of E-MTAB-6389, TCGA-CHOL and GSE26566 were obtained from ArrayExpress, The Cancer Genome Atlas and the Gene Expression Omnibus databases, respectively. Bioinformatic analyses were performed to screen novel biomarkers for predicting the prognosis of iCCA patients. Using multivariate Cox regression analyses, a 3-gene signature (BTD-FER-COL12A1) with potential prognostic value was identified and validated in both a training cohort and two validation cohorts. Results: A total of 177 iCCA patients were included in this study. From the key gene modules significantly associated with liver cirrhosis and overall survival (OS) of iCCA patients, we identified 89 hub genes for functional analyses. Cox-regression analyses in both the training and validation cohort indicate that FER, COL12A1 and BTD were independent risk factors for iCCA patients. A 3-gene signature (BTD-FER-COL12A1) with independent prognostic value in iCCA patients was validated in the training cohort, as well as in two validation cohorts. In terms of predicting the prognosis of iCCA patients, the receiver operating characteristics (ROC) curves showed that this 3-gene signature had superior prediction power to BTD, FER, and COL12A1 alone, as well as known biomarkers (MUC1, MUC13) of iCCA. Immunohistochemical staining of samples from The Human Protein Atlas showed that FER and COL12A1 were positively expressed in iCCA tissue, although BTD was not, while none of these genes was detected in normal tissue. These findings were consistent with the expression status of BTD, FER and COL12A1 at the transcriptional level. In addition, we found that FER and COL12A1 were significantly associated with the degree of infiltration by tumor-infiltrating immune cells. Conclusion: We discovered a three-gene signature with independent prognostic value as a novel biomarker for prediction prognosis of iCCA patients. Our findings may help to find novel therapeutic targets for precision treatment of iCCA.

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“…Recently, five novel mutations and one heterozygous linkage for the c.250-1G>C and c.878dupT variants were discovered in eight symptomatic patients from China, resulting in decreased protein expression due to structural damage and affecting BTD enzyme activity ( 15 , 16 ). In the present study, using homology modeling of BTD, we confirmed that replacement of ARG with CYS is deleterious and results in a non-functional BTD enzyme.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Reveals a Missense Variant c.1612C>T (p.Arg538Cys) in the BTD Gene Leading to Neuromyelitis Optica Spectrum Disorder in Saudi Families

et al. 2022

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Biotinidase deficiency is an autosomal recessive, multiple carboxylase deficiency usually associated with seizures, eczema, hypotonia, visual disturbances, hearing loss, and developmental delays. Only a handful of cases of biotinidase deficiency that had clinical features of neuromyelitis optica spectrum disorder have been reported in the literature. The case report study is about the clinical and genetic features of two pediatric patients from different families with biotinidase deficiency whose brain and spine MRI scans were suggestive of neuromyelitis optica. Neither child improved with immunotherapy. They come from a first-degree blood-related family. In both cases, a deficiency of the enzyme biotinidase was detected. The missense variant NM_001370658.1 (BTD):c.1612C>T (p.Arg538Cys) NM_000060.4 in exon 4 was identified by whole-exome sequencing. The identified sequence variation was validated using Sanger sequencing analysis. The intake of biotin resulted in clinical improvement. After a follow-up period of 12 months, the patient was gradually weaned from tracheostomy. His vision had improved significantly. He was able to walk and run independently. In conclusion, biotinidase deficiency is a rare and treatable cause of neuromyelitis optica. Early diagnosis can prevent poor clinical outcomes. Biotinidase enzyme levels should be considered as part of the examination algorithm for neuromyelitis optica spectrum disorder.

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Clinical features, BTD gene mutations, and their functional studies of eight symptomatic patients with biotinidase deficiency from Southern China

Cited by 12 publications

References 32 publications

Identification and Characterization of BTD Gene Mutations in Jordanian Children with Biotinidase Deficiency

Identification and Characterization of BTD Gene Mutations in Jordanian Children with Biotinidase Deficiency

Identification of a Three-gene Signature Acting as a Novel Prognostic Biomarker in Intrahepatic Cholangiocarcinoma Patients

Whole-Exome Sequencing Reveals a Missense Variant c.1612C>T (p.Arg538Cys) in the BTD Gene Leading to Neuromyelitis Optica Spectrum Disorder in Saudi Families

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