Diabetic ketoacidosis in vanishing white matter

Alamri, Hannadi; Mutairi, Fuad Al; Alothman, Johara; Alothaim, Ali; Alfadhel, Majid; Alfares, Ahmed

doi:10.1002/ccr3.597

Cited by 7 publications

(9 citation statements)

References 10 publications

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“…While PNDM associated with heterozygous eIF2Bα variants do not exhibit severe neurological features, two reported cases displayed mild learning disability or attention deficit disorder [181], highlighting the link between cognitive abilities and eIF2B, which was discussed previously.…”

Section: Eif2b Mutations and Their Link To Neonatal Diabetessupporting

confidence: 54%

“…The VWMD mutations are predominantly located in the C-terminal of eIF2Bα and appear to disrupt the formation of the eIF2B decamer, whereas PNDM mutations occur within the N-terminal region and appear to disrupt activation of the ISR [37,179]. However, interestingly in a VWMD patient that exhibited diabetic ketoacidosis, the homozygous missense variant was present in the N-terminal (eIF2Bα L49R ) [181], which would suggest a similar eIF2Bα defect observed in PNDM mutations and could explain the diabetic presentation.…”

Section: Eif2b Mutations and Their Link To Neonatal Diabetesmentioning

confidence: 99%

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Regulation and function of elF2B in neurological and metabolic disorders

et al. 2022

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Eukaryotic initiation factor 2B, eIF2B is a guanine nucleotide exchange, factor with a central role in coordinating the initiation of translation. During stress and disease, the activity of eIF2B is inhibited via the phosphorylation of its substrate eIF2 (p-eIF2α). A number of different kinases respond to various stresses leading to the phosphorylation of the alpha subunit of eIF2 and collectively this regulation is known as the Integrated Stress Response, ISR. This targeting of eIF2B allows the cell to regulate protein synthesis and reprogramme gene expression to restore homeostasis. Advances within structural biology have furthered our understanding of how eIF2B interacts with eIF2 in both the productive GEF active form and the non-productive eIF2ɑ phosphorylated form. Here, current knowledge of the role of eIF2B in the ISR is discussed within the context of normal and disease states focussing particularly on diseases such as Vanishing White Matter Disease (VWMD) and Permanent Neonatal Diabetes Mellitus (PNDM), which are directly linked to mutations in eIF2B. The role of eIF2B in synaptic plasticity and memory formation is also discussed. In addition, the cellular localisation of eIF2B is reviewed and considered along with the role of additional in vivo eIF2B binding factors and protein modifications that may play a role in modulating eIF2B activity during health and disease.

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Section: Eif2b Mutations and Their Link To Neonatal Diabetessupporting

confidence: 54%

Section: Eif2b Mutations and Their Link To Neonatal Diabetesmentioning

confidence: 99%

Regulation and function of elF2B in neurological and metabolic disorders

et al. 2022

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“…Conversely, Wolcott-Rallison syndrome is caused by EIF2AK3 mutations [6] that lead to less PERKmediated eIF2α phosphorylation. Mutations in EIF2B1, that cause diabetes and liver dysfunction, impair the interaction between P-eIF2α and eIF2B and may attenuate signaling in the PERK branch [8,39]. These diseases highlight the crucial role of PERK signaling and proper protein synthesis and folding to the function of secretory cells, including beta cells, neurons, chondrocytes and osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

DNAJC3 deficiency induces β-cell mitochondrial apoptosis and causes syndromic young-onset diabetes

Lytrivi

Senée

Salpea

et al. 2021

European Journal of Endocrinology

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Objective: DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome. Methods: Whole exome sequencing was performed and identified variants were confirmed by Sanger sequencing. DNAJC3 was silenced by RNA interference in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells. β-cell function and apoptosis were assessed, and potential mediators of apoptosis examined. Results: The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities. They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3. DNAJC3 silencing did not impair insulin content or secretion. Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA. Conclusions: This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response. DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis.

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“…VWM is a progressive condition, usually fatal in childhood. Extraneurological features are generally not present, although diabetic ketoacidosis at 8 months was reported in one patient with a homozygous p.(Leu49Arg) variant in EIF2B1 (14). None of the five patients we report had severe neurological features; however, case subject 4 has a mild learning disability and case subject 5 has attention deficit disorder.…”

Section: Discussionmentioning

confidence: 67%

De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

et al. 2020

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Permanent neonatal diabetes mellitus (PNDM) is caused by reduced b-cell number or impaired b-cell function. Understanding of the genetic basis of this disorder highlights fundamental b-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex a subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for b-cells and highlight EIF2B1's fundamental role within this pathway.

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Diabetic ketoacidosis in vanishing white matter

Abstract: Key Clinical MessageClinicians should consider the EIF2B1 gene defect in any patient with diffuse white matter disease on an MRI of the brain and DKA.

Cited by 7 publications

References 10 publications

Regulation and function of elF2B in neurological and metabolic disorders

Regulation and function of elF2B in neurological and metabolic disorders

DNAJC3 deficiency induces β-cell mitochondrial apoptosis and causes syndromic young-onset diabetes

De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

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