Homozygous mutation, p.Pro304His, in IDH3A, encoding isocitrate dehydrogenase subunit is associated with severe encephalopathy in infancy

Fattal‐Valevski, Aviva; Eliyahu, Hila; Fraenkel, NItai D.; Elmaliach, Ganit; Hausman-Kedem, Moran; Shaag, Avraham; Mandel, Dror; Pines, Ophry; Elpeleg, Orly

doi:10.1007/s10048-016-0507-z

Cited by 29 publications

(23 citation statements)

References 17 publications

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“…47 Moreover, it is well known that homozygous or compound heterozygous mutations in TCA-cycle-related genes (e.g., SDH genes, FH, MDH2, ACO2 [MIM: 100850], IDH3A [MIM: 601149], or SLC25A10), lead to encephalopathy and neurodegeneration. [48][49][50][51][52] Thus, if one takes into account the evidences linking intermediary metabolism, tumorigenesis, and neurodegeneration, it is not surprising to find that mutations in DLST lead to cancer.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13 C 5 -glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals ($7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.

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Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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“…IDH3 catalyzes the oxidation of isocitrate to α-ketoglutarate in the citric acid cycle, also known as the Krebs cycle. Recently, a homozygous missense IDH3A variant, p.(Pro304His) was found in a patient suffering from severe infantile encephalopathy with peripheral and autonomic nervous system involvement 20 . Funduscopy at the age of 8 months revealed RP and bilateral optic atrophy.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma

et al. 2017

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Purpose To identify the genetic cause and describe the phenotype in four families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. Design Case series. Subjects Seven patients from four unrelated families with arRP of which three patients had bilateral early-onset macular pseudocoloboma. Methods We performed homozygosity mapping and whole-exome sequencing (WES) in five probands and two unaffected family members of four unrelated families. Subsequently, Sanger sequencing and segregation analysis were done in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography (ffERG), fundus photography, fundus autofluorescence imaging and optical coherence tomography. Main Outcome Measures IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, ffERG, fundus autofluorescence and OCT findings. Results We identified seven different variants in IDH3A in four unrelated families, i.e. five missense, one nonsense and one frameshift variant. All subjects developed symptoms early in life ranging from night blindness to decreased visual acuity and were diagnosed between the ages of one and 11 years. Four subjects with biallelic IDH3A variants displayed a typical arRP phenotype and three subjects were diagnosed with arRP and pseudocoloboma of the macula. Conclusions IDH3A variants were identified as a novel cause of typical arRP, in some individuals associated with macular pseudocoloboma. We observed both phenotypes in two siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

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“…This mutation was confirmed pathogenic in our study and that comes with agreement to another study that confirmed the association of P304H mutation with sever encephalopathy in infancy. (28) GeneMANIA revealed that IDH3A interacts with so many genes and functions in the cellular respiration and energy derivation by oxidation of organic compounds in the tricaboxylic acid cycle, and abnormalities in this function was found to play a key role in the pathogenesis of Bipolar Disorder, therefore IDH3A could potentially be a novel therapeutic target for bipolar disorder. (29) The genes co-expressed with, share similar protein domain, or participate to achieve similar function were illustrated by GeneMANIA and shown in figure (2) Tables (4 & 5).…”

Section: Resultmentioning

confidence: 99%

“…Our study is the first in silico analysis of IDH3A gene. It was based on functional analysis while all previous studies (25,28) were based on exome sequencing. The 20 deleterious SNPs might be considered as a potential novel target in the diagnosis of Retinitis Pigmentosa and associated diseased.…”

Section: Resultmentioning

confidence: 99%

In silico analysis ofIDH3Agene revealed Novel mutations associated with Retinitis Pigmentosa

Mahmoud¹,

Abdelmoneim²,

Murshed³

et al. 2019

Preprint

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Background: Retinitis Pigmentosa (RP) refers to a group of inherited disorders characterized by the death of photoreceptor cells leading to blindness. The aim of this study is to identify the pathogenic SNPs in the IDH3A gene and their effect on the structure and function of the protein. Method: we used different bioinformatics tools to predict the effect of each SNP on the structure and function of the protein. Result: 20 deleterious SNPs out of 178 were found to have a damaging effect on the protein structure and function. Conclusion: this is the first in silico analysis of IDH3A gene and 20 novel mutations were found using different bioinformatics tools, and they could be used as diagnostic markers for Retinitis Pigmentosa.Keywords: Retinitis Pigmentosa (RP), IDH3A, SNP, in silico analysis, diagnostic markers.RP has three patterns of inheritance; autosomal dominant (adRP), autosomal recessive (arRP) and X-linked pattern (14,(20)(21)(22) and the most reported genes for each case are RHO gene, USH2A and RPGR respectively (4, 21-24) yet the gene we are working on, Isocitrate Dehydrogease 3, (IDH3A) is a novel gene identified as the cause of typical arRP (25) located in the human chromosome 15q25.1 (26). The IDH3A function is to catalyze the oxidative decarboxylation of isocitrate (27) which is the key rate-limiting step of the tricarboxylic acid cycle. It also plays a central role in the aerobic energy production and cellular respiration thus mutations in this gene will affect the nervous system (28, 29) and may cause cancer (30,31).Although the RP is the most common inherited disease of the retina (14, 32-36) there is still no effective therapeutic strategy and the exact pathogenesis and etiology of the disease is not clear (3,5,32,37).The aim of this study is to identify the pathogenic SNPs in the IDH3A gene and their effect on the structure and function of the protein, which might help in the overall understanding of the pathogenesis of the disease and could be used as diagnostic markers. This is the first in silico analysis in the coding region of IDH3A gene to prioritize SNPs for further genetic mapping studies. Utilization of in analysis softwares expedites the process of identifying the deleterious SNPs with no cost, and also facilitates future genetic studies. (38)

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Homozygous mutation, p.Pro304His, in IDH3A, encoding isocitrate dehydrogenase subunit is associated with severe encephalopathy in infancy

Cited by 29 publications

References 17 publications

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma

In silico analysis ofIDH3Agene revealed Novel mutations associated with Retinitis Pigmentosa

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