Loss-of-Function Variants in SUPT5H as Modifying Factors in Beta-Thalassemia

Abstract

It is well known that modifiers play a role in ameliorating or exacerbating disease phenotypes in patients and carriers of recessively inherited disorders such as sickle cell disease and thalassemia. Here, we give an overview of the literature concerning a recently described association in carriers of SUPT5H Loss-of-Function variants with a beta-thalassemia-like phenotype including the characteristic elevated levels of HbA₂. That SUPT5H acts as modifier in beta-thalassemia carriers became evident from three reported cases in whom combined heterozygosity of SUPT5H and HBB gene variants was observed to resemble a mild beta-thalassemia intermedia phenotype. The different SUPT5H variants and hematologic parameters reported are collected and reviewed to provide insight into the possible effects on hematologic expression, as well as potential disease mechanisms in carriers and patients.

Keywords: SUPT5H; beta-thalassemia; hematology; hemoglobin; modifying factor; molecular diagnosis; β-thalassemia intermedia.

Figure 1

Schematic presentation of the SUPT5H gene. The white boxes are the untranslated regions, and the black boxes are the coding exons. Arrows indicate the position and HGVS annotation of the variants. The protein structure is shown below from left (N-terminus) to right (C-terminus). The functional domains are the acidic region, the NGN domain which interacts with Spt4, the five KOW domains (Kyrpides–Ouzounis–Woese domains), two C-terminal repeat domains (CTR-1 and CTR-2) which can be phosphorylated and, finally, two KOW domains (KOW6 and 7). The numbers below the domains indicate the amino acid (a.a.) positions in the protein chain and the arrows correspond with the arrows in the upper graph, indicating the a.a. position of each variant.

Figure 2

Schematic presentation of the effect of reduced SUPT5H expression in carriers and in double heterozygous beta-thalassemia trait carriers. The SUPT5H gene is indicated as an open box, HBB and HBA1/2 genes as blue and red boxes respectively. The proteins are indicated below the genes as oval (Spt5h) and circles (alpha-/beta-globin). The tetramer represents hemoglobin HbA, the yellow arrows at the genes indicate the reduced levels of expression and reduction of protein synthesis, the curved lines indicate a suspected influence of reduced Spt5h synthesis on the HBB expression, for which the exact mechanism is unknown.

Figure 3

(a). Mean and 95% range of red cell indices for reference values from Dacie and Lewis, Practical Haematology 12th ed. [32], β-thalassemia carriers from Weatherall and Clegg, The Thalassemia Syndromes 4th ed. (1), SUPT5H carriers and double heterozygous carriers of SUPT5H and HBB variants (Table S1). (a). Hb (g/L) mean ± 2SD for reference group of men is 150 ± 20 g/L and that for women is 135 ± 15 g/L; Hb (g/L) mean ± 2SD for SUPT5H carriers is 119.5 g/L (91–149 g/L), which overlaps largely with the Hb of β-thalassemia carriers (men, 118 ± 15 g/L, and women, 108 ± 9.0 g/L). Mean Hb level of double heterozygote β-thalassemia and SUPT5H carriers is 98 g/L (SD = 2.89). (b). Mean MCV of reference men and women is 92 ± 9 femtoliter; the MCV of SUPT5H carriers is 79 femtoliter (69–91); the MCV of β-thalassemia carriers is 70.5 + 4.2 fl. The mean MCV of double heterozygote β-thalassemia and SUPT5H carriers is 53.3 femtoliter (SD = 6.35). (c). Mean MCH of reference is 29.5 ± 2.5 picogram, that of β-thalassemia carriers is 21.5 ± 1.3 picogram and that of SUPT5H carriers is 25.60 picogram (21.6–27.4). Mean MCH of double heterozygote β-thalassemia and SUPT5H carriers is 16.6 (SD = 1.42). (d). Mean HbA₂ percentage for reference group is 2.2–3.5, mean HbA₂% of SUPT5H carriers is 5.2% (3.6–6.4), and mean HbA₂% of β carriers is 4.9 ± 0.5%. Mean of HbA₂% for double heterozygote β-thalassemia and SUPT5H carriers is 10.67% (SD = 1.99).