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. 2019 Jun;21(6):1286-1294.
doi: 10.1038/s41436-018-0340-x. Epub 2018 Oct 19.

Biallelic GALM pathogenic variants cause a novel type of galactosemia

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
Free article

Biallelic GALM pathogenic variants cause a novel type of galactosemia

Yoichi Wada et al. Genet Med. 2019 Jun.
Free article

Erratum in

  • Correction: Biallelic GALM pathogenic variants cause a novel type of galactosemia.
    Wada Y, Kikuchi A, Arai-Ichinoi N, Sakamoto O, Takezawa Y, Iwasawa S, Niihori T, Nyuzuki H, Nakajima Y, Ogawa E, Ishige M, Hirai H, Sasai H, Fujiki R, Shirota M, Funayama R, Yamamoto M, Ito T, Ohara O, Nakayama K, Aoki Y, Koshiba S, Fukao T, Kure S. Wada Y, et al. Genet Med. 2020 Jul;22(7):1281. doi: 10.1038/s41436-020-0836-z. Genet Med. 2020. PMID: 32499603

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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Comment in

  • Type IV galactosemia.
    Timson DJ. Timson DJ. Genet Med. 2019 Jun;21(6):1283-1285. doi: 10.1038/s41436-018-0359-z. Epub 2018 Nov 21. Genet Med. 2019. PMID: 30459459 No abstract available.

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