![]() ![]() Informed consent was obtained from the patients’ parents or legal guardians, and the study protocol was approved by the regional independent ethics committee and the French Ministry of Research (DC 2014-2272/2015/ DC-2008-329). The study was conducted in accordance with French legislation and the principles of the Declaration of Helsinki. Methods Patients and human cord blood samples Taken as a whole, our data demonstrate that a dominant gain-of-function (GOF) mutation in the GDP/GTP binding site of the RAC2 protein inhibits HSPC differentiation and leads to a severe AD form of SCID with a clinical presentation of RD. 11, 12 Using biochemical and in vitro differentiation assays, we demonstrated that the RAC2 mutation was closely related to an impairment in cell differentiation capacity and defects in cellular and mitochondrial networks. 8-10 Unlike the other members of the Rac subfamily (RAC1 and RAC3), RAC2 is mostly expressed on hematopoietic cells. There, active RAC2 protein triggers various signaling pathways until the GTP is hydrolyzed following binding to GTPase-activating proteins (GAP). Upon stimulation and activation by guanine nucleotide exchange factors, the active RAC2-GTP-bound form translocates to the plasma membrane. In the inactive GDP-bound state, RAC2 is located in the cytosol. RAC2 belongs to the Rac subfamily of RHO small GTPases. ![]() We have identified an autosomal dominant (AD) missense mutation in the RAC2 gene (coding for Ras-related C3 botulinum toxin substrate 2 ) in three SCID patients whose clinical presentation overlaps with the RD SCID but who lack AK2 mutations and deafness. The high AK2 expression levels in the inner ear may also account for the sensorineural hearing loss observed in patients with RD. 4We and others have previously demonstrated that bi-allelic mutations in the gene coding for adenylate kinase 2 (AK2) are involved in the RD phenotype by disrupting the ATP production required to sustain the survival and differentiation of hematopoietic stem/progenitor cells (HSPC). In addition to the hematopoietic defect, patients with RD have bilateral sensorineural deafness. Reticular dysgenesis (RD) is the SCID form with the earlier clinical presentation (i.e., a few days after birth), due to the absence of both neutrophils and T cells. ![]() Less than 5% of SCID patients do not have a molecular diagnosis. 1 At present, all the SCID with a known molecular defect have an autosomal recessive pattern of inheritance or, in one case, Xlinked inheritance. The only curative treatments are allogeneic hematopoietic stem cell transplantation (HSCT) or, for two types of SCID, autologous gene-modified HSCT. Life-threatening SCID are the most severe primary immunodeficiencies in the absence of treatment, SCID lead to death within the first year of life. Severe combined immunodeficiencies (SCID) are inherited primary immunodeficiencies characterized by a profound impairment of T-cell development and an intrinsic or functional defect in the B-cell compartment. Therefore, screening for RAC2 gain-of-function mutations should be considered in patients with a SCID phenotype and who lack a molecular diagnosis. The results of in vitro differentiation assays showed that RAC2 is essential for the survival and differentiation of hematopoietic stem/progenitor cells. Biochemical assays showed that the mutation was associated with a gain of function. This mutation was de novo in the index case, who had been cured by hematopoietic stem cell transplantation but had transmitted the mutation to her sick daughter. In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R). They are defined by the absence of autologous T cells and the presence of an intrinsic or extrinsic defect in the B-cell compartment. Severe combined immunodeficiencies (SCIDs) constitute a heterogeneous group of life-threatening genetic disorders that typically present in the first year of life. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |