A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing
Background: Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) is a rare mitochondrial disease caused by mutations in the GTPBP3 gene. The rare incidence of the disease and the high clinical heterogeneity pose challenges in making a precise diagnosis. Investigations into the rare COXPD23 pat...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024032304 |
| _version_ | 1797224258700574720 |
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| author | Yanjun Wang Juan He Fangling Dong Weihua Shou Xingxing Feng Ya Yang Cuifen Li Jingjing Wang Bin Li Shufang Xiao |
| author_facet | Yanjun Wang Juan He Fangling Dong Weihua Shou Xingxing Feng Ya Yang Cuifen Li Jingjing Wang Bin Li Shufang Xiao |
| author_sort | Yanjun Wang |
| collection | DOAJ |
| description | Background: Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) is a rare mitochondrial disease caused by mutations in the GTPBP3 gene. The rare incidence of the disease and the high clinical heterogeneity pose challenges in making a precise diagnosis. Investigations into the rare COXPD23 patients are of pathophysiological and etiological value. In this study, we investigated the genotype-phenotype relationship in a COXPD23 patient from a Manchu family, with GTPBP3 mutations. Methods: Routine physical examinations, laboratory assays and imaging analyses were performed. The metabolic profiles of amino acids in blood, acylcarnitine in blood and organic acids in urine were used to determine the presence of inherited metabolic diseases. Genetic variations in the family were investigated using whole-exome sequencing and Sanger sequencing. Splicing disruption by a mutation was predicted and verified using a minigene assay. Results: The patient presented with severe lactic acidosis, neurological symptoms, multiple symmetrical lesions in the brain and serious mitochondrial energy metabolism disturbances. The c.689A > C (p.Q230P) and c.809-1_809delinsA compound heterozygous mutations were detected in GTPBP3. The novel c.809-1_809delinsA mutation was located at the splicing site of exon 7 and intron 6 and multiple tools predicted that it would disrupt the normal splicing. The minigene assay proved that the novel mutation resulted in two aberrant transcripts that created premature termination codons. Conclusions: The clinical manifestations, brain imaging change, mitochondrial metabolism disturbances and the detection and validation of the GTPBP3 mutations expand the profile of COXPD23 and the pathogenic mutation spectrum. Our study improves the understanding of the pathophysiology and etiology of COXPD23. |
| first_indexed | 2024-04-24T13:50:16Z |
| format | Article |
| id | doaj.art-46aea6830ec34a51a1caf63b637448f9 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-24T13:50:16Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-46aea6830ec34a51a1caf63b637448f92024-04-04T05:04:27ZengElsevierHeliyon2405-84402024-03-01106e27199A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicingYanjun Wang0Juan He1Fangling Dong2Weihua Shou3Xingxing Feng4Ya Yang5Cuifen Li6Jingjing Wang7Bin Li8Shufang Xiao9Pediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, ChinaPediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, ChinaPediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, ChinaKunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, ChinaDepartment of Clinical Laboratory, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, ChinaPediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, ChinaPediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, ChinaPediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, ChinaPediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, China; Corresponding author.Pediatric Intensive Care Unit, Kunming Children's Hospital, Children's Hospital Affiliated to Kunming Medical University, Kunming, China; Corresponding author.Background: Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) is a rare mitochondrial disease caused by mutations in the GTPBP3 gene. The rare incidence of the disease and the high clinical heterogeneity pose challenges in making a precise diagnosis. Investigations into the rare COXPD23 patients are of pathophysiological and etiological value. In this study, we investigated the genotype-phenotype relationship in a COXPD23 patient from a Manchu family, with GTPBP3 mutations. Methods: Routine physical examinations, laboratory assays and imaging analyses were performed. The metabolic profiles of amino acids in blood, acylcarnitine in blood and organic acids in urine were used to determine the presence of inherited metabolic diseases. Genetic variations in the family were investigated using whole-exome sequencing and Sanger sequencing. Splicing disruption by a mutation was predicted and verified using a minigene assay. Results: The patient presented with severe lactic acidosis, neurological symptoms, multiple symmetrical lesions in the brain and serious mitochondrial energy metabolism disturbances. The c.689A > C (p.Q230P) and c.809-1_809delinsA compound heterozygous mutations were detected in GTPBP3. The novel c.809-1_809delinsA mutation was located at the splicing site of exon 7 and intron 6 and multiple tools predicted that it would disrupt the normal splicing. The minigene assay proved that the novel mutation resulted in two aberrant transcripts that created premature termination codons. Conclusions: The clinical manifestations, brain imaging change, mitochondrial metabolism disturbances and the detection and validation of the GTPBP3 mutations expand the profile of COXPD23 and the pathogenic mutation spectrum. Our study improves the understanding of the pathophysiology and etiology of COXPD23.http://www.sciencedirect.com/science/article/pii/S2405844024032304COXPD23Novel GTPBP3 mutationWhole exome sequencingMinigeneMitochondrial diseases |
| spellingShingle | Yanjun Wang Juan He Fangling Dong Weihua Shou Xingxing Feng Ya Yang Cuifen Li Jingjing Wang Bin Li Shufang Xiao A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing Heliyon COXPD23 Novel GTPBP3 mutation Whole exome sequencing Minigene Mitochondrial diseases |
| title | A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing |
| title_full | A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing |
| title_fullStr | A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing |
| title_full_unstemmed | A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing |
| title_short | A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing |
| title_sort | novel mutation in gtpbp3 causes combined oxidative phosphorylation deficiency 23 by affecting pre mrna splicing |
| topic | COXPD23 Novel GTPBP3 mutation Whole exome sequencing Minigene Mitochondrial diseases |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024032304 |
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