Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency.

Autor:	Zhen X; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center., Betti M; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center., Kars ME; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai., Patterson A; Division of Molecular Pathogenesis, Department of Medicine, Vanderbilt University Medical Center., Medina-Torres EA; Immune deficiencies laboratory, National Institute of Pediatrics, Health Secretariat., Scheffler Mendoza SC; Clinical Immunology Service, National Institute of Pediatrics, Health Secretariat., Herrera Sánchez DA; Specialty Hospital, National Medical Center XXI Century., Lopez-Herrera G; Immune deficiencies laboratory, National Institute of Pediatrics, Health Secretariat., Svyryd Y; Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán., Mutchinick O; Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán., Gamazon E; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center., Rathmell J; Division of Molecular Pathogenesis, Department of Medicine, Vanderbilt University Medical Center., Itan Y; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai., Markle J; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center., O'Farrill Romanillos P; Specialty Hospital, National Medical Center XXI Century., Lugo-Reyes SO; Immune deficiencies laboratory, National Institute of Pediatrics, Health Secretariat., Martinez-Barricarte R; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Jul 11. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.21203/rs.3.rs-4595246/v1
Abstrakt:	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. Competing Interests: Competing Interests The authors declare that they have no relevant conflicts of interest. Additional Declarations: No competing interests reported.
Databáze:	MEDLINE
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