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The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis.

ABSTRACT: A recessive mutation named Justy was found that abolishes B lymphopoiesis but does not impair other major aspects of hematopoiesis. Transplantation experiments showed that homozygosity for Justy prevented hematopoietic progenitors from generating B cells but did not affect the ability of bone marrow stroma to support B lymphopoiesis. In bone marrow from mutant mice, common lymphoid progenitors and pre-pro-B cells appeared normal, but cells at subsequent stages of B lymphopoiesis were dramatically reduced in number. Under culture conditions that promoted B lymphopoiesis, mutant pre-pro-B cells remained alive and began expressing the B cell marker CD19 but failed to proliferate. In contrast, these cells were able to generate myeloid or T/NK precursors. Genetic and molecular analysis demonstrated that Justy is a point mutation within the Gon4-like (Gon4l) gene, which encodes a protein with homology to transcriptional regulators. This mutation was found to disrupt Gon4l pre-mRNA splicing and dramatically reduce expression of wild-type Gon4l RNA and protein. Consistent with a role for Gon4l in transcriptional regulation, the levels of RNA encoding C/EBPalpha and PU.1 were abnormally high in mutant B cell progenitors. Our findings indicate that the Gon4l protein is required for B lymphopoiesis and may function to regulate gene expression during this process.

SUBMITTER: Lu P

PROVIDER: S-EPMC2901076 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis.

Lu Ping P Hankel Isaiah L IL Knisz Judit J Marquardt Andreas A Chiang Ming-Yi MY Grosse Johannes J Constien Rainer R Meyer Thomas T Schroeder Andreas A Zeitlmann Lutz L Al-Alem Umaima U Friedman Ann D AD Elliott Eric I EI Meyerholz David K DK Waldschmidt Thomas J TJ Rothman Paul B PB Colgan John D JD

The Journal of experimental medicine 20100607 7

A recessive mutation named Justy was found that abolishes B lymphopoiesis but does not impair other major aspects of hematopoiesis. Transplantation experiments showed that homozygosity for Justy prevented hematopoietic progenitors from generating B cells but did not affect the ability of bone marrow stroma to support B lymphopoiesis. In bone marrow from mutant mice, common lymphoid progenitors and pre-pro-B cells appeared normal, but cells at subsequent stages of B lymphopoiesis were dramaticall ...[more]

PMID: 20530203

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Project description:BackgroundHuman hypomorphic nuclear factor-kappaB essential modulator (NEMO) mutations cause diverse clinical and immunologic phenotypes, but understanding of their scope and mechanistic links to immune function and genotype is incomplete.ObjectiveWe created and analyzed a database of hypomorphic NEMO mutations to determine the spectrum of phenotypes and their associated genotypes and sought to establish a standardized NEMO reconstitution system to obtain mechanistic insights.MethodsPhenotypes of 72 individuals with NEMO mutations were compiled. NEMO L153R and C417R were investigated further in a reconstitution system. TNF-alpha or Toll-like receptor (TLR)-5 signals were evaluated for nuclear factor-kappaB activation, programmed cell death, and A20 gene expression.ResultsThirty-two different mutations were identified; 53% affect the zinc finger domain. Seventy-seven percent were associated with ectodermal dysplasia, 86% with serious pyogenic infection, 39% with mycobacterial infection, 19% with serious viral infection, and 23% with inflammatory diseases. Thirty-six percent of individuals died at a mean age of 6.4 years. CD40, IL-1, TNF-alpha, TLR, and T-cell receptor signals were impaired in 15 of 16 (94%), 6 of 7 (86%), 9 of 11 (82%), 9 of 14 (64%), and 7 of 18 (39%), respectively. Hypomorphism-reconstituted NEMO-deficient cells demonstrated partial restoration of NEMO functions. Although both L153R and C417R impaired TLR and TNF-alpha-induced NF-kappaB activation, L153R also increased TNF-alpha-induced programmed cell death with decreased A20 expression.ConclusionDistinct NEMO hypomorphs define specific disease and genetic characteristics. A reconstitution system can identify attributes of hypomorphisms independent of an individual's genetic background. Apoptosis susceptibility in L153R reconstituted cells defines a specific phenotype of this mutation that likely contributes to the excessive inflammation with which it is clinically associated.

Dataset Information

The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis.

Publications

The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis.

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