Albertine Donker

Chapter 9 316 KNOWLEDGE GAPS CONCERNING IRON REFRACTORY IRON DEFICIENCY ANEMIA The genetic and molecular background of IRIDA needs further elucidation The genetic aspects and molecular pathways underlying the pathogenesis of IRIDA are poorly understood. In our IRIDA case series ( Chapter 4 2 ) 14 out of 21 of our IRIDA patients had a homozygous or compound heterozygous TMPRSS6 defect, consistent with an autosomal recessive disease, in line with the majority of IRIDA cases that have been described in the literature. 1 However, in the other seven patients both Sanger sequencing and Multiplex ligation-dependent probe amplification (MLPA) identified only a heterozygous TMPRSS6 defect, challenging the idea of Mendelian inheritance due to rare TMPRSS6 variants with a high penetrance. These findings corroborate previous reports of mono-allelic patients presenting with an IRIDA phenotype (reviewed in 1 ). Also, the question remains whether others and we did not miss small deletions or insertions in the coding sequences, defects in the introns and promoter region or balanced translocations of chromosome 22, affecting expression or function of the wild type considered allele. Several IRIDA probands in our series in whom only a heterozygous TMPRSS6 defect was found, had first-degree relatives without an IRIDA phenotype but with identical TMPRSS6 genotypes, supporting this hypothesis. Moreover, the results of parental haplotype analysis that we performed in two IRIDA families suggested that differences in phenotype between probands and unaffected siblings with the same heterozygous TMPRSS6 defect could be attributed to differences in the as wild type considered inherited parental allele, also supporting this idea. Apart from still undetected pathogenic variants in this as wild type considered TMPRSS6 allele, cis -acting mechanisms may also explain the different phenotypes in IRIDA patients and individuals with identical TMPRSS6 genotypes. Epigenetic processes as imprinting, involving DNA and histone methylation, are known to influence mRNA transcription and may result in a difference concerning the relative expression of the paternal-inherited versus the maternal-inherited allele. 72 Furthermore, the presence of polymorphisms in regulatory elements of the TMPRSS6 gene may play a role in these cis -acting mechanisms. 72 Interestingly, mice studies indicate that expression of HAMP is regulated by histone acetylation and de- acetylation, 73 suggesting that indeed epigenetic phenomena may play a role in the etiology of IRIDA. In addition to the above-mentioned genetic factors, environmental