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

LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure

“…In addition to LARS2, variants in several other genes encoding components of the mitochondrial protein translation apparatus result in sideroblastic anemia, including YARS2, PUS1 (MLASA1; OMIM 600462), TRNT1 (SIFD; OMIM 616084), and deletions of genes encoding mttRNAs responsible for Pearson syndrome (OMIM #557000) (Bottomley and Fleming 2014;Chakraborty et al 2014). However, the mechanistic basis as to why variants in genes involved in mitochondrial protein translation cause sideroblastic anemia and such a broad phenotypic spectrum remains elusive.…”

Inherited Immunodeficiency: A New Association With Early-Onset Childhood Panniculitis

“…9 Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency (B-cell lymphopenia), periodic fevers, and developmental delay. 10 Mutations in the NF-κB2 gene cause the recently defined clinical syndrome, common variable immunodeficiency, with central adrenal insufficiency. 11 Thus, the occurrence of autoinflammatory panniculitis expands the phenotypes associated with mutations in TRNT1 and NF-κB2.…”

A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia

“…All genetically defined congenital SAs (CSAs) can be attributed to mutations in 1 of 3 mitochondrial pathways: heme synthesis, iron-sulfur cluster biogenesis and protein synthesis, or, rarely, a mutation in a protein involved in mitochondrial respiration itself. 2,4 Other than X-linked SA and ataxia, which is due to an iron-sulfur biogenesis defect, each of the genetically defined syndromic CSA phenotypes (thiamine-responsive megaloblastic anemia; Pearson marrowpancreas syndrome; mitochondrial myopathy with lactic acidosis and ringed sideroblasts; and SA, immunodeficiency, fevers, and developmental delay 5,6 ) is associated with a generalized defect in mitochondrial protein translation or synthesis of a specific mitochondrial protein.…”