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Functional analysis of naturally occurring amino acid substitutions in human IFN-gammaR1.

Abstract：

:IFN-gamma plays an essential role in the IL-12/IL-23/IFN-gamma pathway that is required for the defense against intracellular pathogens. In the IFN-gammaR1 several amino acid substitutions have been reported that abrogate IFN-gamma signaling. These substitutions can lead to a null phenotype and enhanced susceptibility to infection by poorly pathogenic mycobacteria, a disorder known as Mendelian Susceptibility to Mycobacterial Disease (MSMD). More common amino acid variations in the IFN-gammaR1 may also influence IFN-gammaR function, albeit more subtle. To determine the effect of various amino acid substitutions on IFN-gammaR1 expression and function we cloned two newly identified amino acid substitutions (S149L, I352M), four common variations (V14M, V61I, H335P, L467P), seven reported missense mutations (V61Q, V63G, Y66C, C77Y, C77F, C85Y, I87T) and the 818delTTAA mutation in a retroviral expression vector. IFN-gammaR1 expression was determined as well as responsiveness to IFN-gamma stimulation. The two newly discovered variants, and the four common polymorphisms could be detected on the cell surface, however, the V14M, H335P and I352M variants were significantly lower expressed at the cell membrane, compared to the wild type receptor. Despite the variance in cell surface expression, these IFN-gammaR1 variants did not affect function. In contrast to literature, in our model the expression of the V63G variant was severely reduced and its function was severely impaired but not completely abrogated. In addition, we confirmed the severely reduced function of the I87T mutant receptor, the completely abrogated expression and function of the V61E, V61Q, C77F, C77Y and the C85Y mutations, as well as the overexpression pattern of the 818delTTAA mutant receptor. The Y66C mutation was expressed at the cell surface, it was however, not functional. We conclude that the V14M, V61I, S149L, H335P, I352M and L467P are functional polymorphisms. The other variants are deleterious mutations with V61E, V61Q, Y66C, C77F, C77Y and C85Y leading to complete IFN-gammaR1 deficiency, while V63G and I87T lead to partial IFN-gammaR1 deficiency.

journal_name

Mol Immunol

journal_title

Molecular immunology

authors

van de Wetering D,de Paus RA,van Dissel JT,van de Vosse E

doi

10.1016/j.molimm.2009.11.016

subject

Has Abstract

pub_date

2010-02-01 00:00:00

pages

1023-30

issue

eissn

0161-5890

issn

1872-9142

pii

S0161-5890(09)00843-8

journal_volume

pub_type

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Functional analysis of naturally occurring amino acid substitutions in human IFN-gammaR1.