Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).

Abstract

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.

• Authors: Pranesh K Chakraborty, Klaus Schmitz-Abe, Erin K Kennedy, Hapsatou Mamady, Turaya Naas, Danielle Durie, Dean R Campagna, Ashley Lau, Anoop K Sendamarai, Daniel H Wiseman, Alison May, Stephen Jolles, Philip Connor, Colin Powell, Matthew M Heeney, Patricia-Jane Giardina, Robert J Klaassen, Caroline Kannengiesser, Isabelle Thuret, Alexis A Thompson, Laura Marques, Stephen Hughes, Denise K Bonney, Sylvia S Bottomley, Robert F Wynn, Ronald M Laxer, Caterina P Minniti, John Moppett, Victoria Bordon, Michael Geraghty, Paul B M Joyce, Kyriacos Markianos, Adam D Rudner, Martin Holcik, Mark D Fleming
• Journal: Blood (Blood) Vol. 124 Issue 18 Pg. 2867-71 (Oct 30 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 25193871 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA Nucleotidyltransferases
• tRNA nucleotidyltransferase

Topics

• Alleles
• Anemia, Sideroblastic (complications, congenital, enzymology, genetics)
• Developmental Disabilities (complications, genetics)
• Fever (complications, genetics)
• Genetic Diseases, X-Linked (complications, enzymology, genetics)
• HEK293 Cells
• Humans
• Immunologic Deficiency Syndromes (complications, genetics)
• Mutation (genetics)
• RNA Nucleotidyltransferases (genetics)