Dyschromatosis symmetrica hereditaria and reticulate acropigmentation of Kitamura: An update

Abstract

Dyschromatosis symmetrica hereditaria (DSH) and reticulate acropigmentation of Kitamura (RAK) are rare, inherited pigmentary diseases. DSH shows a mixture of pigmented and depigmented macules on the extremities. RAK shows reticulated, slightly depressed pigmented macules on the extremities. The causative gene of DSH was clarified as ADAR1 by positional cloning including linkage analysis and haplotype analysis in 2003. Ten years later, the causative gene of RAK was identified as ADAM10 by wholeexome sequencing, in 2013. ADAR1 is an RNA-editing enzyme which catalyzes the deamination of adenosine to inosine (A-to-I) in double-stranded RNA substrates during post-transcription processing. Inosine acts as guanine during translation, resulting in codon alterations or alternative splice sites that lead to functional changes in proteins when they occur in coding regions. In 2012, it was clarified that ADAR1 mutations cause Aicardi-Goutières syndrome 6, which is a severe genetic inflammatory disease that affects the brain and the skin. A zinc metalloprotease, a disintegrin and metalloprotease domaincontaining protein 10 (ADAM10), is involved in the ectodomain shedding of various membrane proteins and shows various functions in vivo. ADAM10 is known to be involved in the ectodomain shedding of Notch proteins as substrates in the skin. We speculate that the pathogenesis of RAK and Dowling-Degos disease (DDD, a pigmentary disease similar to RAK) is associated with the Notch signaling pathway. In addition, ADAM10 mutations proved to be associated with late-onset Alzheimer disease. This review comprehensively discusses the updated pathophysiology of those genetic pigmentary disorders.

Pathogenesis of a variant in the 5′ untranslated region of ADAR1 in dyschromatosis symmetrica hereditaria

“…Although DSH is known to result from the haploinsufficiency of ADAR1 (Kono & Akiyama, ), the present assay showed only mild haploinsufficiency. The gene expressions with c.‐60A>G of ADAR1 are 73% and 43% of that of the wild type.…”

“…DSH is characterized by a mixture of hyper‐ and hypopigmented small macules on the dorsal aspects of the extremities. The disorder commonly develops during infancy or early childhood (Kono & Akiyama, ). We know that some DSH patients show clinically typical DSH skin manifestations, but the causative mutations have not been identified in coding regions or exon–intron boundary regions of ADAR1 .…”

The role of RNA editing enzyme ADAR1 in human disease

“…Interestingly, Gly1007Arg mutation was described in DSH patients who had neurodegeneration and intracranial calcification, symptoms also found in AGS. While all but two of the AGS mutations were missense, DSH mutants included missense, truncating, insertion/deletion, and inframe mutations in both coding and untranslated regions (Kono & Akiyama, 2019; Rice et al, 2012; Suganuma et al, 2020). Haploinsufficiency from these stop or frameshift mutations may be the cause for the autosomal dominance of DSH.…”

A mark of disease: how mRNA modifications shape genetic and acquired pathologies

“…Missense mutations in ADAR1 cause Aicardi-Goutières Syndrome, a childhood autoimmune encephalitis characterized by increased interferon (Rice et al 2012;Gallo et al 2017). Mutations in ADAR1 are also associated with Dyschromatosis Symmetrica Hereditaria (DSH), a rare autosomal genetic disorder of the skin, but the pathogenetic mechanisms are not yet clear (Miyamura et al 2003;Kono and Akiyama 2019).…”