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A Novel Pathogenic Variant in PRF1 Associated with Hemophagocytic Lymphohistiocytosis

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Abstract

Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL2) results from mutations in PRF1. We described two unrelated individuals who presented with FHL, in whom severely impaired NK cytotoxicity and decrease perforin expression was observed. DNA sequencing of PRF1 demonstrated that both were not only heterozygous for the p.54R > C/91A > V haplotype but also presented with the novel variant p.47G > V at the perforin protein. Perforin mRNA was found to be increased in a individual with that genotype. A carrier of the novel variant also demonstrated altered perforin mRNA and protein expression. Phylogenetic analysis and multiple alignments with perforin orthologous demonstrated a high level of conservation at Gly47. PolyPhen-2 and PROVEAN predicted p.47G > V to be “probably damaging” and “deleterious”, respectively. A thermodynamic analysis showed that this variant was highly stabilizing, decreasing the protein internal energy. The ab initio perforin molecular modeling indicated that Gly47 is buried inside the hydrophobic core of the MACPF domain, which is crucial for the lytic pore formation and protein oligomerization. After the in silico induction of the p.47G > V mutation, Val47 increased the interactions with the surrounding amino acids due to its size and physical properties, avoiding a proper conformational change of the domain. To our knowledge, this is the first description supporting that p.47G > V is a pathogenic variant that in conjunction with p.54R > C/91A > V might result in the clinical phenotype of FHL2.

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Acknowledgments

We are grateful to the patients’ families and healthy control volunteers involved in this study for their participation and cooperation. JAP acknowledges the grants from Vicerrectoría de Investigación (CIQF-177) and Estrategia de Sostenibilidad 2013–2014, Universidad de Antioquia. We thank Javier Rendón for his medical advice. This study was supported by the Colombian Institute for the development of Science and Technology, COLCIENCIAS (Grant #111556934426) and Estrategia de Sostenibilidad 2011–2012, Vicerrectoría de Investigaciones-Universidad de Antioquia, Medellin- Colombia.

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Authors and Affiliations

  1. Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia

    Camilo Andrés Pérez Romero, Isaura Pilar Sánchez, Sebastian Gutierrez-Hincapié, Jesús A. Álvarez-Álvarez, José Luis Franco Restrepo & Claudia Milena Trujillo-Vargas

  2. Programa de Estudio y Control en Enfermedades Tropicales, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia

    Rodrigo Ochoa & Carlos Enrique Muskus-López

  3. Programa de Ofidismo/Escorpionismo, Facultad de Química Farmacéutica, Universidad de Antioquia, Medellín, Colombia

    Jaime Andres Pereañez

  4. Grupo de Reumatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia

    Ruth G. Eraso

  5. Departamento de Pediatría, Hospital San Vicente Fundación, Universidad de Antioquia, Medellín, Colombia

    Catalina Arango

  6. Hospital Pablo Tobón Uribe, Medellín, Colombia

    Ruth G. Eraso & Carolina Echeverry

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  1. Camilo Andrés Pérez Romero
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Correspondence to Claudia Milena Trujillo-Vargas.

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Romero, C.A.P., Sánchez, I.P., Gutierrez-Hincapié, S. et al. A Novel Pathogenic Variant in PRF1 Associated with Hemophagocytic Lymphohistiocytosis. J Clin Immunol 35, 501–511 (2015). https://doi.org/10.1007/s10875-015-0169-x

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  • DOI: https://doi.org/10.1007/s10875-015-0169-x

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