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

Duanwu Zhang, Tao Yue, Jin Huk Choi, Evan Nair-Gill, Xue Zhong, Kuan wen Wang, Xiaoming Zhan, Xiaohong Li, Mihwa Choi, Miao Tang, Jiexia Quan, Sara Hildebrand, Eva Marie Y. Moresco, Bruce Beutler

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalNature Immunology
DOIs
StateAccepted/In press - Jan 1 2019

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Spliceosomes
Immune System Diseases
Alleles
Hematopoietic Stem Cells
U5 Small Nuclear Ribonucleoproteins
Muromegalovirus
Messenger RNA
Essential Genes
Lymphoid Tissue
Introns
Cell Differentiation
Proteins
T-Lymphocytes
Cell Line
Mutation
Infection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Syndromic immune disorder caused by a viable hypomorphic allele of spliceosome component Snrnp40. / Zhang, Duanwu; Yue, Tao; Choi, Jin Huk; Nair-Gill, Evan; Zhong, Xue; Wang, Kuan wen; Zhan, Xiaoming; Li, Xiaohong; Choi, Mihwa; Tang, Miao; Quan, Jiexia; Hildebrand, Sara; Moresco, Eva Marie Y.; Beutler, Bruce.

In: Nature Immunology, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Nair-Gill, Evan

AU - Zhong, Xue

AU - Wang, Kuan wen

AU - Zhan, Xiaoming

AU - Li, Xiaohong

AU - Choi, Mihwa

AU - Tang, Miao

AU - Quan, Jiexia

AU - Hildebrand, Sara

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AU - Beutler, Bruce

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