skip to main content
Idioma:
Primo Search
Clear Search Box
Search in: Búsqueda General
Búsqueda Avanzada
Búsqueda por Índices

A cell-based functional assay that accurately links genotype to phenotype in familial HLH

Noori, Tahereh ; Rudd-Schmidt, Jesse A. ; Kane, Alisa ; Frith, Katie ; Gray, Paul E. ; Hu, Hannah ; Hsu, Danny ; Chung, Clara W. T. ; Hodel, Adrian W. ; Trapani, Joseph A. ; Voskoboinik, Ilia

Blood, 2023-05, Vol.141 (19), p.2330-2342 [Revista revisada por pares]

United States: Elsevier Inc

Texto completo disponible

Citas Citado por
  • Título:
    A cell-based functional assay that accurately links genotype to phenotype in familial HLH
  • Autor: Noori, Tahereh ; Rudd-Schmidt, Jesse A. ; Kane, Alisa ; Frith, Katie ; Gray, Paul E. ; Hu, Hannah ; Hsu, Danny ; Chung, Clara W. T. ; Hodel, Adrian W. ; Trapani, Joseph A. ; Voskoboinik, Ilia
  • Materias: Animals ; Genotype ; Humans ; Lymphohistiocytosis, Hemophagocytic - diagnosis ; Lymphohistiocytosis, Hemophagocytic - genetics ; Membrane Proteins - genetics ; Mice ; Munc18 Proteins - genetics ; Mutation ; Perforin - genetics ; Phenotype ; Pore Forming Cytotoxic Proteins
  • Es parte de: Blood, 2023-05, Vol.141 (19), p.2330-2342
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descripción: •Novel approach identifies pathogenicity of PRF1, UNC13D, STX11, and STXBP2 mutations and accurately distinguishes familial and acquired HLH. [Display omitted] Familial forms of the severe immunoregulatory disease hemophagocytic lymphohistiocytosis (HLH) arise from biallelic mutations in the PRF1, UNC13D, STXBP2, and STX11 genes. Early and accurate diagnosis of the disease is important to determine the most appropriate treatment option, including potentially curative stem cell transplantation. The diagnosis of familial HLH (FHL) is traditionally based on finding biallelic mutations in patients with HLH symptoms and reduced natural killer (NK)–cell cytotoxicity. However, patients often have a low NK-cell count or receive immunosuppressive therapies that may render the NK-cell cytotoxicity assay unreliable. Furthermore, to fully understand the nature of a disease it is critical to directly assess the effect of mutations on cellular function; this will help to avoid instances in which carriers of innocuous mutations may be recommended for invasive procedures including transplantation. To overcome this diagnostic problem, we have developed a rapid and robust method that takes advantage of the functional equivalence of the human and mouse orthologues of PRF1, UNC13D, STX11, and STXBP2 proteins. By knocking out endogenous mouse genes in CD8+ T cells and simultaneously replacing them with their mutated human orthologues, we can accurately assess the effect of mutations on cell function. The wide dynamic range of this novel system allowed us to understand the basis of, otherwise cryptic, cases of FHL or HLH and, in some instances, to demonstrate that previously reported mutations are unlikely to cause FHL. This novel approach provides valuable new information to enable more accurate diagnosis and treatment of patients with HLH or FHL who inherit mutations of undetermined pathogenicity. Familial hemophagocytic lymphohistiocytosis (fHLH) is a severe immunoregulatory disease arising from biallelic loss-of-function mutations in genes necessary for normal T-cell and natural killer cell cytotoxicity. Noori and colleagues address the vexing issue of the activity of variants of uncertain significance (VUS) in known fHLH genes. The authors describe a novel cell-based system for characterizing VUS by transfecting them into murine CD8 cells that have a knockout of the cognate gene to determine if the human gene complements the functional defects. Though complex, this approach provides better diagnosis and pathogenetic insights into rare potentially pathogenic variants.
  • Editor: United States: Elsevier Inc
  • Idioma: Inglés
Enlaces
Volver a la lista de resultados

  • Realización: ABCD-USP USP   Logos de Redes Sociales: Freepik

Buscando en bases de datos remotas, por favor espere

  • Buscando por
  • enscope:(USP_PRODUCAO),scope:(USP_EBOOKS),scope:("PRIMO"),scope:(USP),scope:(USP_EREVISTAS),scope:(USP_FISICO),primo_central_multiple_fe
  • Mostrar lo que tiene hasta ahora