Syndromic immune disorder caused by a viable hypomorphic allele of spliceosome component Snrnp40

We report a new immunodeficiency disorder in mice caused by a viable hypomorphic mutation of Snrnp40 , an essential gene encoding a subunit of the U5 small nuclear ribonucleoprotein (snRNP) complex of the spliceosome. Snrnp40 is ubiquitous but strongly expressed in lymphoid tissue. Homozygous mutant mice showed hypersusceptibility to infection by murine cytomegalovirus and multiple defects of lymphoid development, stability and function. Cell-intrinsic defects of hematopoietic stem cell differentiation also affected homozygous mutants. SNRNP40 deficiency in primary hematopoietic stem cells or T cells or the EL4 cell line increased the frequency of splicing errors, mostly intron retention, in several hundred messenger RNAs. Altered expression of proteins associated with immune cell function was also observed in Snrnp40 -mutant cells. The immunological consequences of SNRNP40 deficiency presumably result from cumulative, moderate effects on processing of many different mRNA molecules and secondary reductions in the expression of critical immune proteins, yielding a syndromic immune disorder. Beutler and colleagues identify skywarp (swp) mice, which exhibit a hypomorphic variant of the U5 splicing protein SNRNP40 and aberrant mRNA splicing specifically in lymphocytes and hematopoietic stem and progenitor cells, suggesting alternative splicing influencing immune cell function.