Identification of a novel childhood hematopoietic failure syndrome caused by combined mutations in ADH5 and ALDH2 that function in aldehyde metabolism.

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K15243
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human genetics
• Research Institution: Kyoto University
• Principal Investigator: HIRA Asuka 京都大学, 放射線生物研究センター, 研究員 (30772777)
• Co-Investigator(Renkei-kenkyūsha): SAITO Megumu 京都大学, iPS細胞研究所, 准教授 (90535486)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: アルデヒド / ADH5 / ALDH2 / 小児骨髄不全

Outline of Final Research Achievements

Here we report a set of Japanese children (total six cases) with hypoplastic anemia and MDS who carried biallelic ADH5 gene mutations and monoallelic ALDH2*504Lys. Hematologically they were similar to FA but they displayed neither overt physical malformation nor increased levels of MMC-induced chromosome breakages.
To test the requirements of these genes for hematopoiesis in vitro, we destroyed these genes in human iPS cells derived from a healthy individual. The iPS cells lacking either ADH5 or ALDH2 showed normal in vitro differentiation potential into hematopoietic lineages, while drastic reduction was observed in ADH5-/-ALDH2+/- iPS cells. Furthermore, the patient derived iPS cells showed decreased colony numbers in clonogenic progenitor assay, which was reversed by exogenous expression of ADH5 or by treatment of cells with ALDH2 agonist drug Alda-1. These results prove the digenic origin of this disorder, and provide a potential therapeutic means for these patients.

Free Research Field

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