Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

Abstract

Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5−/−Aldh2E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

Trigenic ADH5/ALDH2/ADGRV1 mutations in myelodysplasia with Usher syndrome

“…The patient also was heterozygous for a maternally inherited variant (c.1510G>A) in ALDH2 (NM_000690.4), predicted to yield an amino-acid residue substitution (p.Glu504Lys) contributing to functional deficiency of formaldehyde detoxification ( Figure 2 A and B). Both these variants are reported ( Oka et al., 2020 ). These variants were confirmed by Sanger sequencing using highly specific primers to detect only ADH5 rather than variation in a pseudogene.…”

“…Many mechanisms protect the genome from formaldehyde. Endogenous formaldehyde clearance is especially important for normal hematopoiesis ( Dingler et al., 2020 ; Oka et al., 2020 ). Our patient was homozygous for a variant in ADH5 and heterozygous/wild-type for a variant in ALDH2 , whereas DNA crosslink repair genes were intact.…”

“…The rs671 polymorphism protects against alcoholism, but also is associated with an increased risk of cardiovascular disorders and certain types of cancer. Furthermore, in combination with mutations in ADH5 the rs671 polymorphism causes a newly named disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome, as do other ALDH2 variants ( Oka et al., 2020 ).…”

Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells

“…Recent studies show that ALDH2 and ADH5 function together to clear endogenous formaldehyde during HSC differentiation to prevent immune depletion in mouse and induced pluripotent stem cells (iPSCs), as well as in patients with biallelic ALDH2 and ADH5 mutations (Dingler et al 2020;Oka et al 2020;Shen et al 2020;Mu et al 2021) (Fig. 3c).…”

“…Aldehyde-processing enzymes are viewed as essential clearing agents that rapidly deactivate harmful aldehydes, and also as markers of somatic and cancer stem cell populations (O'Brien et al 2005;Marcato et al 2011;Pontel et al 2015;Garaycoechea et al 2018). In the bone marrow, two specific enzymes, aldehyde dehydrogenase (ALDH) 2 and alcohol dehydrogenase (ADH) 5, protect hematopoietic stem cells (HSCs) from endogenous formaldehyde accumulation and toxicity (Dingler et al 2020;Nakamura et al 2020;Oka et al 2020;Jung and Smogorzewska 2021;Mu et al 2021). The importance of aldehyde detoxification in human biology is exemplified by the genetic variants of ALDH2 in the human population, such as the single nucleotide polymorphism r671 in ALDH2 (c.1510G>A; p.E504K; ALDH2*2), which confers loss-of-function in 560 million people, mainly of East Asian origin (Chen et al 2014;Chen et al 2020).…”