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

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.

Read More on PubMed