Gene defects in the soma: some get it and some don’t!
Bernice Lo, Michael J. Lenardo
Bernice Lo, Michael J. Lenardo
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):16-19. https://doi.org/10.1172/JCI45664.
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Commentary

Gene defects in the soma: some get it and some don’t!

Abstract

Advances in DNA sequencing technologies have increased attention on genetic variation in somatic tissues. Although long known to cause neoplastic diseases, somatic variation is now being investigated as a pathogenetic mechanism for other diseases. Somatic changes are genomic DNA variations that were not inherited but arise in tissues throughout life. In this issue of the JCI, Magerus-Chatinet et al. explore somatic changes in patients with autoimmune lymphoproliferative syndrome (ALPS), a congenital disease of defective apoptosis and autoimmunity that is usually associated with germline heterozygous mutations in the gene encoding the Fas death receptor. They explain why certain individuals have severe disease manifestations by documenting somatic alterations in the germline normal FAS allele in an unusual population of “double-negative” T cells found in ALPS. Thus, the oncological concept of somatic loss of heterozygosity leading to selected cell expansion also applies to autoimmune diseases.

Authors

Bernice Lo, Michael J. Lenardo

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Figure 1

Fas receptor and its proximal signaling components.

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Fas receptor and its proximal signaling components. (A) Trimers of Fas l...
(A) Trimers of Fas ligand bind and oligomerize Fas receptor. Fas binds FAS-associated death domain protein (FADD), which recruits caspases 8 and 10, leading to their cleavage and activation. Mutations causing ALPS have been discovered in the genes encoding Fas, Fas ligand, and caspase 10. (B) FAS has 9 exons. Mutations in the portion of the gene encoding the intracellular domains, especially those affecting the death domain, often result in a more severe clinical disease with greater penetrance than those that affect the extracellular domains. (C) Mitotic recombination results in the somatic loss of the wild-type allele giving rise to cells homozygous for the FAS mutation that then have a survival advantage.