학술논문
Biallelic GALM pathogenic variants cause a novel type of galactosemia
Document Type
Original Paper
Author
Wada, Yoichi; Kikuchi, Atsuo; Arai-Ichinoi, Natsuko; Sakamoto, Osamu; Takezawa, Yusuke; Iwasawa, Shinya; Niihori, Tetsuya; Nyuzuki, Hiromi; Nakajima, Yoko; Ogawa, Erika; Ishige, Mika; Hirai, Hiroki; Sasai, Hideo; Fujiki, Ryoji; Shirota, Matsuyuki; Funayama, Ryo; Yamamoto, Masayuki; Ito, Tetsuya; Ohara, Osamu; Nakayama, Keiko; Aoki, Yoko; Koshiba, Seizo; Fukao, Toshiyuki; Kure, Shigeo
Source
Genetics in Medicine: Official journal of the American College of Medical Genetics and Genomics. 21(6):1286-1294
Subject
Language
English
ISSN
1098-3600
1530-0366
1530-0366
Abstract
Purpose: Galactosemia is caused by metabolic disturbances at various stagesof galactose metabolism, including deficiencies in enzymes involved in theLeloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology ofgalactosemia has not been identified in a subset of patients. This study aimedto explore the causes of unexplained galactosemia.Methods: Trio-based exome sequencing and/or Sanger sequencing was performedin eight patients with unexplained congenital galactosemia. In vitro enzymaticassays and immunoblot assays were performed to confirm the pathogenicity of thevariants.Results: The highest blood galactose levels observed in each patient were17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eightpatients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46,p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzesepimerization between β- and α-D-galactose in the first step of the Leloirpathway. GALM enzyme activities were undetectable in lymphoblastoid cell linesestablished from two patients. Immunoblot analysis showed the absence of theGALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALMexpression and protein stability assays revealed altered stabilities of thevariant GALM proteins.Conclusion: Biallelic GALM pathogenicvariants cause galactosemia, suggesting the existence of type IVgalactosemia.