Mutationsingenes encoding proteins that are in volved 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 maturationofboth nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations resultin partial lossoffunction of TRNT1 and lead to metabolic defectsinboth the mitochondria and cytosol, which can account for the phenotypic pleiotropy.
ASJC Scopus subject areas
- Cell Biology