Seda ÇAKMAKLI, Çiğdem BUĞAN KAPLAN, Mehmet UZUNOĞLU, Merve BÜYÜKBAYRAM, Emel GÖRGÜLÜ, Nurten ÖZKAN ZARİF, Ebru KESKİN

A novel homozygous nonsense mutation (p.Y78*) in TMPRSS6 gene causing iron-refractory iron deficiency anemia (IRIDA) in two siblings

Iron-refractory iron deficiency anemia (IRIDA) is an inherited iron metabolism disorder caused by mutations in TMPRSS6 gene encoding matriptase-2, which results in increased hepcidin synthesis. The hallmarks of the disease are hypochromic microcytic anemia, low transferrin saturation, slightly low or normal ferritin levels in contrast to classic iron deficiency anemia (IDA), inadequate response to oral iron, and only a partial response to parenteral iron. We report here a 6-year-old Syrian boy with unexplained microcytic anemia since one year of age. Genetic analysis of the TMPRSS6 gene revealed a novel homozygous nonsense mutation in exon 3 (c.234C>G; p.Y78* or p.Tyr78*). In the presence of hypochromic microcytic anemia accompanied by atypical iron parameters not in accordance with classic IDA, and inadequate response to iron therapy, IRIDA should be remembered in the differential diagnosis.

PDF

___

1.Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008; 40: 569-571.

2.Heeney MM, Finberg KE. Iron-refractory iron deficiency anemia (IRIDA). Hematol Oncol Clin North Am 2014; 28: 637-652.

3.Shokrgozar N, Golafshan HA. Molecular perspective of iron uptake, related diseases, and treatments. Blood Res 2019; 54: 10-16.

4.Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutation Taster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11: 361-362.

5.Camaschella C. How I manage patients with atypical microcytic anaemia. Br J Haematol 2013; 160: 12-24.

6.Brissot P, Bernard DG, Brissot E, Loréal O, Troadec MB. Rare anemias due to genetic iron metabolism defects. Mutat Res 2018; 777: 52-63.

7.Azad SM, Kapoor R, Bannerji R, Ray J, Mitra M. Celiac disease masquerading as refractory iron deficiency anemia. Int J Contemp Pediatr 2017; 4: 672-673.

8.Arsenault V, Mailloux C, Bonnefoy A, Lemyre E, Pastore Y. Iron-refractory iron deficiency anemia may not lead to neurocognitive dysfunction: a case report. Pediatrics 2016; 138: e20153608.

9.Yılmaz Keskin E, Yenicesu I. Iron-refractory iron deficiency anemia. Turk J Haematol 2015; 32: 1-14.

10.Nai A, Pagani A, Silvestri L, Camaschella C. Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood 2010; 116: 851-852. 57.

11.Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 2010; 115: 3817-3826.

12.Melis MA, Cau M, Congiu R, et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica 2008; 93: 1473-1479.

13.Maquat LE. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 2004; 5: 89-99.

14.Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 2007; 76: 51-74.

15.De Falco L, Silvestri L, Kannengiesser C, et al. Functional and clinical impact of novel TMPRSS6variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies. Hum Mutat 2014; 35: 1321-1329.

16.De Falco L, Sanchez M, Silvestri L et al. Iron refractory iron deficiency anemia. Haematologica 2013; 98: 845-853.