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

Chakraborty, P. K.; Schmitz-Abe, K.; Kennedy, E. K.; Mamady, H.; Naas, T.; Durie, D.; Campagna, D. R.; Lau, A.; Sendamarai, A. K.; Wiseman, D. H.; May, A.; Jolles, S.; Connor, P.; Powell, C.; Heeney, M. M.; Giardina, P. J.; Klaassen, R. J.; Kannengiesser, C.; Thuret, I.; Thompson, A. A.; Marques, L.; Hughes, S.; Bonney, D. K.; Bottomley, S. S.; Wynn, R. F.; Laxer, R. M.; Minniti, C. P.; Moppett, J.; Bordon, V.; Geraghty, M.; Joyce, P. B.; Markianos, K.; Rudner, A. D.; Holcik, M.; Fleming, M. D.

Blood. 2014 Sep 7; 124(18):2867-71


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.

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