A Novel Mutation in G6PC3 Gene Associated Non-syndromic Severe Congenital Neutropenia

Khera, Sanjeev; Pramanik, Suman; Patnaik, Saroj Kumar

doi:10.1007/s13312-020-1861-3

Cited by 4 publications

(9 citation statements)

References 6 publications

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“…The G6PC3 variant found in our patient and in his sister was on exon 1 p.E65A (c.194A>C) region 8. A new nonsyndromic mutation was defined on Exon 3 9. Only 6 patients with nonsyndromic mutations were reported in the literature 9.…”

Section: Discussionmentioning

confidence: 62%

“…A new nonsyndromic mutation was defined on Exon 3 9. Only 6 patients with nonsyndromic mutations were reported in the literature 9. The sister of our index case was nonsyndromic as well.…”

Section: Discussionmentioning

confidence: 94%

“…The estimated prevalence of severe congenital neutropenia characterized by a maturation arrest of the myeloid series is 1 in 6 million people 9. The prevalence of mutated genes among patients with severe congenital neutropenia varies according to the ethnicity of and consanguinity rate in the populations.…”

Section: Discussionmentioning

confidence: 99%

“…The estimated prevalence of severe congenital neutropenia characterized by a maturation arrest of the myeloid series is 1 in 6 million people. 9 The prevalence of mutated genes among patients with severe congenital neutropenia varies according to the ethnicity of and consanguinity rate in the populations. G6PC3 deficiency is the third most frequent cause of congenital neutropenia in Turkish Congenital Neutropenia Registry with a prevalence of 4.2% after ELANE and HAX mutations.…”

Section: Discussionmentioning

confidence: 99%

“…10 To date, more than 90 cases with this deficiency have been reported so far. 9,11 In G6PC3 deficiency, the defect in the recycling of glucose from the endoplasmic reticulum to the cytoplasm leads to neutrophil apoptosis. 1 G6PC3 gene is located on 17q21 and has 6 exons.…”

Section: Discussionmentioning

confidence: 99%

See 4 more Smart Citations

Amyloidosis in a Patient With Congenital Neutropenia Because of G6PC3 Deficiency

Yıldırmak

Özçelik²,

Ozagari

et al. 2021

Journal of Pediatric Hematology/Oncology

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Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is a recently identified form of congenital neutropenia associated with developmental anomalies. The severity of neutropenia and the clinical spectrum are highly variable. Aside from infectious complications and extrahematologic features, inflammatory bowel disease and autoinflammatory complications are less frequently observed manifestations. However, amyloidosis has never been reported in G6PC3 deficiency. Here, we present a 12-year-old patient with incidentally discovered neutropenia because of the p.E65A (c.194A > C) variant of the G6PC3 gene. He had recurrent aphthae and abdominal pain episodes, and developed nephrotic-range proteinuria, amyloidosis, and end-stage renal failure during follow-up.

show abstract

Section: Discussionmentioning

confidence: 62%

“…A new nonsyndromic mutation was defined on Exon 3 9. Only 6 patients with nonsyndromic mutations were reported in the literature 9. The sister of our index case was nonsyndromic as well.…”

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Amyloidosis in a Patient With Congenital Neutropenia Because of G6PC3 Deficiency

Yıldırmak

Özçelik²,

Ozagari

et al. 2021

Journal of Pediatric Hematology/Oncology

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Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency

Zhen,

Betti,

Kars

et al. 2024

Preprint

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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.

show abstract

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

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.

show abstract

A Novel Mutation in G6PC3 Gene Associated Non-syndromic Severe Congenital Neutropenia

Cited by 4 publications

References 6 publications

Amyloidosis in a Patient With Congenital Neutropenia Because of G6PC3 Deficiency

Amyloidosis in a Patient With Congenital Neutropenia Because of G6PC3 Deficiency

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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