Biallelic GALM pathogenic variants cause a novel type of galactosemia

Genet Med. 2019 Jun;21(6):1286-1294. doi: 10.1038/s41436-018-0340-x.

Yoichi Wada ¹, Atsuo Kikuchi ², Natsuko Arai-Ichinoi ¹, Osamu Sakamoto ¹, Yusuke Takezawa ¹, Shinya Iwasawa ¹, Tetsuya Niihori ³, Hiromi Nyuzuki ⁴, Yoko Nakajima ⁵, Erika Ogawa ⁶, Mika Ishige ⁶, Hiroki Hirai ⁷, Hideo Sasai ⁸, Ryoji Fujiki ⁹, Matsuyuki Shirota ¹⁰, Ryo Funayama ¹¹, Masayuki Yamamoto ¹², Tetsuya Ito ⁵, Osamu Ohara ⁹, Keiko Nakayama ¹¹, Yoko Aoki ³, Seizo Koshiba ¹², Toshiyuki Fukao ⁸, Shigeo Kure ¹ ¹²

Affiliations

1 Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
2 Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan. akikuchi-thk@umin.ac.jp.
3 Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
4 Department of Pediatrics, Niigata University School of Medicine, Niigata, Japan.
5 Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan.
6 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.
7 Department of Pediatrics, Ehime Prefectural Central Hospital, Matsuyama, Japan.
8 Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
9 Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan.
10 Division of Interdisciplinary Medical Sciences, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
11 Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
12 Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

PMID: 30451973 DOI: 10.1038/s41436-018-0340-x

Abstract

Purpose: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in Enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia.

Methods: Trio-based exome Sequencing and/or Sanger Sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants.

Results: The highest blood galactose levels observed in each patient were 17.3-41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM Enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients' peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins.

Conclusion: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.

Keywords

GALM; Leloir pathway; galactose; galactose mutarotase; genetics.

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