Severe congenital neutropenia due to G6PC3 deficiency: early and delayed phenotype in two patients with two novel mutations

Notarangelo, Lucia Dora; Savoldi, Gianfranco; Cavagnini, Sara; Bennato, Veronica; Vasile, Sabrina; Pilotta, Alba; Plebani, Alessandro; Porta, Fulvio

doi:10.1186/s13052-014-0080-8

Cited by 10 publications

(5 citation statements)

References 21 publications

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“…Depending on the underlying genetic cause, additional defects may occur, such as exocrine pancreatic insufficiency in patients with Shwachman-Diamond syndrome (SDS) 1,[2][3][4][5] or cardiac and urogenital malformations in patients harboring G6PC3 mutations. 4,[6][7][8] Mutations in the ELANE and SBDS genes are among the most common genetic aberrations in CN and its syndromic form, SDS, respectively. 4,9 In past years, research increasingly focused on identifying other hitherto unknown mutations in CN patients without established genetic background, eventually leading to the discovery of more than 20 genetic lesions associated with CN.…”

Section: Introductionmentioning

confidence: 99%

SRP54mutations induce congenital neutropenia via dominant-negative effects onXBP1splicing

Schürch

Schaefer

Müller

et al. 2021

Blood

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Heterozygous de novo missense variants of SRP54 were recently identified in patients with congenital neutropenia (CN), displaying symptoms overlapping with Shwachman-Diamond-Syndrome (SDS).1 Here, we investigate srp54 KO zebrafish as the first in vivo model of SRP54 deficiency. srp54-/- zebrafish are embryonically lethal and display, next to severe neutropenia, multi-systemic developmental defects. In contrast, srp54+/- zebrafish are viable, fertile and only show mild neutropenia. Interestingly, injection of human SRP54 mRNAs carrying mutations observed in patients (T115A, T117Δ and G226E) aggravated neutropenia and induced pancreatic defects in srp54+/- fish, mimicking the corresponding human clinical phenotypes. These data suggest that the variable phenotypes observed in patients may be due to mutation-specific dominant negative effects on the functionality of the residual wildtype SRP54 protein. Consistently, overexpression of mutated SRP54 also induced neutropenia in wildtype fish and impaired granulocytic maturation of human promyelocytic HL-60 cells as well as of healthy cord-blood derived CD34+ HSPCs. Mechanistically, srp54 mutant fish and human cells show impaired unconventional splicing of the transcription factor X-box binding protein 1 (Xbp1). Vice-versa, xbp1 morphants recapitulate phenotypes observed in srp54 deficiency and, importantly, injection of spliced, but not unspliced xbp1 mRNA rescues neutropenia in srp54+/- zebrafish. Together, these data indicate that SRP54 is critical for the development of various tissues, with neutrophils reacting most sensitively to SRP54 loss. The heterogenic phenotypes observed in patients, ranging from mild CN to SDS-like disease, may be due to different dominant negative effects of mutated SRP54 proteins on downstream XBP1 splicing, which represents a potential therapeutic target.

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Section: Introductionmentioning

confidence: 99%

SRP54mutations induce congenital neutropenia via dominant-negative effects onXBP1splicing

Schürch

Schaefer

Müller

et al. 2021

Blood

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“…G6PC3 de ciency is a rare genetic disorder with a broad phenotypic spectrum, posing di culties for timely diagnosis. The differential diagnosis process can be particularly complicated for patients with non-syndromic neutropenia or less frequently observed clinical features [40][41][42] . Mutations observed in G6PC3 de cient patients spread across all six exons of the gene 6 .…”

Section: Discussionmentioning

confidence: 99%

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Zhen,

Betti,

Kars

et al. 2024

Preprint

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G6PC3 deficiency is a monogenic immunometabolic disorder that causes syndromic congenital neutropenia. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican origin. Based on the shared haplotypes amongst carriers of the c.210delC mutation, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it originated in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived cells. G6PC3 pathology is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the variant c.210delC impacts glycolysis by performing extracellular flux assays on patient-derived cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3 deficient patients reported in the literature to date, and we found that c.210delC carriers display all prominent clinical features observed in prior G6PC3 deficient patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.

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“…G6PC3 deficiency is a rare genetic disorder with a broad phenotypic spectrum, posing difficulties for timely diagnosis. The differential diagnosis process can be particularly complicated for patients with non-syndromic neutropenia or less frequently observed clinical features [23][24][25] . Mutations observed in G6PC3 deficient patients spread across all six exons of the gene 6 .…”

Section: Discussionmentioning

confidence: 99%

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Zhen,

Betti,

Kars

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Objective: The G6PC3 c.210delC variant has been identified in patients of Mexican origin. We set out to study the origin and functional consequence of this mutation. Furthermore, we sought to characterize the clinical phenotypes caused by it. Methods: Using whole-genome sequencing data, we conducted haplotype analysis to estimate the age of this allele and traced its ancestral origin. We examined how this mutation affected G6PC3 protein expression and performed extracellular flux assays on patient-derived cells to characterize how this mutation impacts glycolysis. Finally, we compared the clinical presentations of patients with the c.210delC mutation relative to other G6PC3 deficient patients published to date. Results: Based on the length of haplotypes shared amongst ten carriers of the G6PC3 c.210delC mutation, we estimated that this variant originated in a common ancestor of indigenous American origin. The mutation causes a frameshift that introduces a premature stop codon, leading to a complete loss of G6PC3 protein expression. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Clinically, c.210delC carriers display all the clinical features of syndromic severe congenital neutropenia type 4 observed in prior reports of G6PC3 deficiency. Conclusion: The G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.

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Severe congenital neutropenia due to G6PC3 deficiency: early and delayed phenotype in two patients with two novel mutations

Cited by 10 publications

References 21 publications

SRP54mutations induce congenital neutropenia via dominant-negative effects onXBP1splicing

SRP54mutations induce congenital neutropenia via dominant-negative effects onXBP1splicing

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

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