Molecular Characteristics
CTU2 (Cytosolic Thiouridylase, Subunit 2) is located at chromosome 16q24.3 and encodes for a cytosolic t-RNA thiouridylase protein, which is a subunit of a highly conserved protein complex involved in modifying uracil at position 34 (U34) in the t-RNA for three amino acids (lysine, glutamate, and glutamine), forming a wobble that ensures the decoding of more than one codon by the same t-RNA species. CTU2 also adds sulfur to U34, which plays a role in maintinaing the stabiliity and fedelity of the wobble.
Mutations and pathophysiology
Deficiency of CTU2 results in a deficiency of sulfurated U34, decreasing the translational efficiency of proteins enriched for the three codons CAA (Gln), AAA (Lys), and GAA (Glu) and increasing the sensitivity to reagents that decrease translational accuracy.
Shaheen et al. (2016) found that three boys from three consanguineous Saudi families who had MFRG syndrome had homozygosity for a c.873 G>A transition (NM_001012762.1) in the CTU2 gene. This transition resulted in a synonymous T247T substitution. The authors demonstrated that the mutation impairs normal splicing, causing a frameshift that leads to a premature termination codon (p.Thr247Alafs*21).
In another study, Shaheen et al. (2016) identified homozygosity for the T247T variant on the same haplotype background in two male cousins from a consanguineous family from the United Arab Emirates with MFRG. The authors noted that the carrier frequency of this founder mutation was 1 in 769 individuals in Saudi Arabia and suggested that the apparently synonymous nature of the causal variant might contribute to the underdiagnosis of this syndrome.
In a large case series, Shaheen et al. (2019) reported 5 new patients with CTU-2 associated syndrome. The study’s cohort revealed that the typical features of MFRG syndrome occurred with the following frequencies: dysmorphic facies (10 out of 10, with cleft seen in 2 out of 10), renal agenesis (5 out of 10), ambiguous genitalia (6 out of 6 males), microcephaly (10 out of 10), polydactyly (3 out of 10), and lissencephaly (4 out of 10). Agenesis of the corpus callosum was common (6 out of 10) as were congenital heart disease (8 out of 10) and epilepsy (6 out of 10). Global developmental delay was a constant feature in all patients who survived beyond early infancy.
CTU2